Disubstituted pyrazolines and triazolines as factor Xa inhibitors

ABSTRACT

The present application describes disubstituted pyrazolines and triazolines of formulae I and II:                    
     or pharmaceutically acceptable salt forms thereof, wherein one of M 1  and M 2  maybe N and D may be a variety of N-containing groups, which are useful as inhibitors of factor Xa.

This application claims the benefit of U.S. Provisional Application No.60/079,725, filed Mar. 27, 1998.

FIELD OF THE INVENTION

This invention relates generally to disubstituted pyrazolines andtriazolines which are inhibitors of trypsin-like serine proteaseenzymes, especially factor Xa, pharmaceutical compositions containingthe same, and methods of using the same as anticoagulant agents fortreatment and prevention of thromboembolic disorders.

BACKGROUND OF THE INVENTION

WO 95/18111 addresses fibrinogen receptor antagonists, containing basicand acidic termini, of the formula:

wherein R¹ represents the basic termini, U is an alkylene or heteroatomlinker, V may be a heterocycle, and the right hand portion of themolecule represents the acidic termini. The presently claimed compoundsdo not contain the acidic termini of WO 95/18111.

In U.S. Pat. No. 5,463,071, Himmelsbach et al depict cell aggregationinhibitors which are 5-membered heterocycles of the formula:

wherein the heterocycle may be aromatic and groups A—B—C— and F—E—D— areattached to the ring system. A—B—C— can be a wide variety ofsubstituents including a basic group attached to an aromatic ring. TheF—E—D— group, however, would appear to be an acidic functionality whichdiffers from the present invention. Furthermore, use of these compoundsas inhibitors of factor Xa is not discussed.

WO 97/47299 describes amidino and guanidino heterocyclic proteaseinhibitors of the formula:

R¹—Z—X—Y—W

wherein W contains an amidino, guanidino, or imino group attached to avariety of moieties including phenyl and piperidinyl, Y is a O, N, S, orC linker or is absent, X is a heterocycle, Z is a two atom linkercontaining at least one heteroatom, and R¹ is a variety of groupsincluding cycloalkyl, aryl, heteroaryl, and araalkyl all of which areoptionally substituted. A variety of proteases are described as possibletargets for these compounds including Factor Xa. The presently claimedcompounds differ in that they do not contain the combination R¹—Z orY—W.

WO 97/23212 describes isoxazolines, isothiazolines, and pyrazolines ofthe formula:

wherein X is O, S or NR¹⁵. Though the pyrazolines of WO 97/23212 areindicated to be factor Xa inhibitors, they are not considered part ofthe present invention.

Activated factor Xa, whose major practical role is the generation ofthrombin by the limited proteolysis of prothrombin, holds a centralposition that links the intrinsic and extrinsic activation mechanisms inthe final common pathway of blood coagulation. The generation ofthrombin, the final serine protease in the pathway to generate a fibrinclot, from its precursor is amplified by formation of prothrombinasecomplex (factor Xa, factor V, Ca²⁺ and phospholipid). Since it iscalculated that one molecule of factor Xa can generate 138 molecules ofthrombin (Elodi, S., Varadi, K.: Optimization of conditions for thecatalytic effect of the factor IXa-factor VIII Complex: Probable role ofthe complex in the amplification of blood coagulation. Thromb. Res.1979, 15, 617-629), inhibition of factor Xa may be more efficient thaninactivation of thrombin in interrupting the blood coagulation system.

Therefore, efficacious and specific inhibitors of factor Xa are neededas potentially valuable therapeutic agents for the treatment ofthromboembolic disorders. It is thus desirable to discover new factor Xainhibitors.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide noveldisubstituted pyrazolines and triazolines which are useful as factor Xainhibitors or pharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

It is another object of the present invention to provide a method fortreating thromboembolic disorders comprising administering to a host inneed of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or a pharmaceuticallyacceptable salt or prodrug form thereof.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat compounds of formulae I and II:

or pharmaceutically acceptable salt or prodrug forms thereof, wherein A,B, D, E, G, M, Z, R^(1a), R^(1b), and s are defined below, are effectivefactor Xa inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in a first embodiment, the present invention provides novelcompounds of formulae I or II:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

M¹ is N or CR^(1c);

M² is NR^(1a) or CR^(1a)R^(1a), provided that only one of M¹ and M² is aN atom;

D is selected from C(═NR⁸)NR⁷R⁹, NHC(═NR⁸)NR⁷R⁹, NR⁸CH(═NR⁷), C(O)NR⁷R⁸,and CR⁸R⁹NR⁷R⁸;

E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,and piperidinyl substituted with 1 R;

alternatively, D—E—G together represent pyridyl substituted with 1 R;

R is selected from H, Cl, F, Br, I, (CH₂)_(t)OR³, C₁₋₄ alkyl, OCF₃, CF₃,C(O)NR⁷R⁸, and (CR⁸R⁹)_(t)NR⁷R⁸;

G is selected from NHCH₂, OCH₂, and SCH₂, provided that when s is 0,then G is absent;

Z is selected from a C₁₋₄ alkylene, (CH₂)_(r)O(CH₂)_(r),(CH₂)_(r)NR³(CH₂)_(r), (CH₂)_(r)C(O)(CH₂)_(r), (CH₂)_(r)C(O)O(CH₂)_(r),(CH₂)_(r)OC(O)(CH₂)_(r), (CH₂)_(r)C(O)NR³(CH₂)_(r),(CH₂)_(r)NR³C(O)(CH₂)_(r), (CH₂)_(r)OC(O)O(CH₂)_(r),(CH₂)_(r)OC(O)NR³(CH₂)_(r), (CH₂)_(r)NR³C(O)O(CH₂)_(r),(CH₂)_(r)NR³C(O)NR³(CH₂)_(r), (CH₂)_(r)S(O)_(p)(CH₂)_(r),(CH₂)_(r)SO₂NR³(CH₂)_(r), (CH₂)_(r)NR³SO₂(CH₂)_(r), and(CH₂)_(r)NR³SO₂NR³(CH₂)_(r), provided that Z does not form a N—N, N—O,N—S, NCH₂N, NCH₂O, or NCH₂S bond with group A;

R^(1a) and R^(1b) are, at each occurrence, independently selected fromH, —(CH₂)_(r)—R^(1′), NCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″),N(CH₂)₂(CH₂)_(t)R^(1′), O(CH₂)₂(CH₂)_(t)R^(1′), andS(CH₂)₂(CH₂)_(t)R^(1′);

R^(1c) is selected from H, —(CH₂)_(q)—R^(1′), C₁₋₃ alkyl, C(O)R^(2c),(CF₂)_(r)CO₂R^(2c), C(O)NR²R^(2a), C₃₋₆ carbocyclic residue substitutedwith 0-2 R⁴, and 5-10 membered heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R⁴;

R^(1′) is selected from H, C₁₋₃ alkyl, halo, (CF₂)_(r)CF₃, OR²,NR²R^(2a), C(O)R^(2c), OC(O)R², (CF₂)_(r)CO₂R^(2c), S(O)_(p)R^(2b),NR²(CH₂)_(r)OR², NR²C(O)R^(2b), NR²C(O)NHR^(2b), NR²C(O)₂R^(2a),OC(O)NR^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂R^(2b), C₃₋₆carbocyclic residue substituted with 0-2 R⁴, and 5-10 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R⁴;

R^(1″) is selected from H, C(O)R^(2b), C(O)NR²R^(2a), S(O)R^(2b),S(O)₂R^(2b), and SO₂NR²R^(2a);

R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl,C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R^(4b);

R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl,C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R^(4b);

R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, C₁₋₆alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and5-6 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R^(4b);

R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and5-6 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R^(4b);

alternatively, R² and R^(2a) combine to form a 5 or 6 memberedsaturated, partially saturated or unsaturated ring substituted with 0-2R^(4b) which contains from 0-1 additional heteroatoms selected from thegroup consisting of N, O, and S;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

A is selected from:

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁴, and

5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R⁴;

B is selected from:

X—Y, NR²R^(2a), C(═NR²)NR²R^(2a), NR²C(═NR²)NR²R^(2a),

C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and

5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R^(4a);

X is selected from C₁₋₄ alkylene, —CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—,—C(═NR)—, —CR²(NR^(1″)R²)—, —CR²(OR²)—, —CR²(SR²)—, —C(O)CR²R^(2a)—,—CR²R^(2a)C(O), —S(O)_(p)—, —S(O)_(p)CR²R^(2a)—, —CR²R^(2a)S(O)_(p)—,—S(O)₂NR²—, —NR²S(O)₂—, —NR²S(O)₂CR²R^(2a)—, —CR²R^(2a)S(O)₂NR²—,—NR²S(O)₂NR²—, —C(O)NR²—, —NR²C(O)—, —C(O)NR²CR²R^(2a)—,—NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—, —NR²C(O)O—,—OC(O)NR²—, —NR²C(O)NR²—, —NR²—, —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O,—CR²R^(2a)O—, and —OCR²R^(2a)—;

Y is selected from:

(CH₂)_(r)NR²R^(2a), provided that X—Y do not form a N—N, O—N, or S—Nbond,

C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and

5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R^(4a);

R⁴, at each occurrence, is selected from ═O, (CH₂)_(r)OR², halo, C₁₋₄alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b),C(O)NR²R^(2a), NR²C(O)NR²R^(2a), CH(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a),SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵,(CF₂)_(r)CF₃, NCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″),N(CH₂)₂(CH₂)_(t)R^(1′), O(CH₂)₂(CH₂)_(t)R^(1′), andS(CH₂)₂(CH₂)_(t)R^(1′),

alternatively, one R⁴ is a 5-6 membered aromatic heterocycle containingfrom 1-4 heteroatoms selected from the group consisting of N, O, and S;

R^(4a), at each occurrence, is selected from ═O, (CH₂)_(r)OR², halo,C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b),NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a), CH(═NR²)NR²R^(2a),NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl,NR²SO₂R⁵, S(O)_(p)R⁵, and (CF₂)_(r)CF₃;

alternatively, one R^(4a) is a 5-6 membered aromatic heterocyclecontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-1 R⁵;

R^(4b), at each occurrence, is selected from ═O, (CH₂)_(r)OR³, halo,C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³,NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O)NR³R^(3a), CH(═NR³)NR³R^(3a),NH³C(═NR³)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl,NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl,S(O)_(p)-phenyl, and (CF₂)_(r)CF₃;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenylsubstituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶;

R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r)OR², halo, C₁₋₄alkyl, CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b),NR²C(O)NR²R^(2a), CH(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a),NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₄ alkyl;

R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, (CH₂)_(n)-phenyl, C₆₋₁₀aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenylC₁₋₄ alkoxycarbonyl;

R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and(CH₂)_(n)-phenyl;

alternatively, R⁷ and R⁸ combine to form a 5 or 6 membered saturated,ring which contains from 0-1 additional heteroatoms selected from thegroup consisting of N, O, and S;

R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and(CH₂)_(n)-phenyl;

n, at each occurrence, is selected from 0, 1, 2, and 3;

m, at each occurrence, is selected from 0, 1, and 2;

p, at each occurrence, is selected from 0, 1, and 2;

q, at each occurrence is selected from 1 and 2;

r, at each occurrence, is selected from 0, 1, 2, and 3;

s, at each occurrence, is selected from 0, 1, and 2; and,

t, at each occurrence, is selected from 0 and 1.

[2] In a preferred embodiment, the present invention provides novelcompounds of formulae Ia-Ib:

wherein;

Z is selected from a CH₂O, OCH₂, CH₂NH, NHCH₂, C(O), CH₂C(O), C(O)CH₂,NHC(O), C(O)NH, CH₂S(O)₂, S(O)₂(CH₂)), SO₂NH, and NHSO₂, provided that Zdoes not form a N—N, N—O, NCH₂N, or NCH₂O bond with group A;

A is selected from one of the following carbocyclic and heterocyclicsystems which are substituted with 0-2 R⁴;

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl,morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl,benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, andisoindazolyl;

B is selected from: Y, X—Y, NR²R^(2a), C(═NR²)NR²R^(2a), andNR²C(═NR²)NR²R^(2a);

X is selected from C₁₋₄ alkylene, —C(O)—, —C(═NR)—, —CR²(NR²R^(2a))—,—C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —C(O)NR²—, —NR²C(O)—,—C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—,—CR²R^(2a)NR²C(O)—, —NR²C(O)NR²—, —NR²—, —NR²CR²R^(2a)—, —CR²R^(2a)NR²—,O, —CR²R^(2a)O—, and —OCR²R^(2a)—;

Y is NR²R^(2a), provided that X—Y do not form a N—N or O—N bond;

alternatively, Y is selected from one of the following carbocyclic andheterocyclic systems which are substituted with 0-2 R^(4a);

cylcopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl,pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl,pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl,isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl,benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl,indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;

alternatively, Y is selected from the following bicyclic heteroaryl ringsystems:

K is selected from O, S, NH, and N.

[3] In a more preferred embodiment, the present invention provides novelcompounds of formulae Ia-Ib, wherein;

Z is selected from a C(O), CH₂C(O), C(O)CH₂, NHC(O), C(O)NH, C(O)N(CH₃),CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided that Z does not form aN—N or NCH₂N bond with group A.

[4] In an even more preferred embodiment, the present invention providesnovel compounds of formulae Ia-Ib, wherein;

E is phenyl substituted with R or 2-pyridyl substituted with R;

D is selected from C(O)NH₂, C(═NH)NH₂, CH₂NH₂, CH₂NHCH₃, CH(CH₃)NH₂, andC(CH₃)₂NH₂; and,

R is selected from H, OCH₃, Cl, and F.

[5] In a further preferred embodiment, the present invention providesnovel compounds of formulae Ia-Ib, wherein;

D—E is selected from 3-amidinophenyl, 3-aminomethylphenyl,3-aminocarbonylphenyl, 3-(methylaminomethyl)phenyl,3-(1-aminoethyl)phenyl, 3-(2-amino-2-propyl)phenyl,4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl,4-chloro-3-(methylaminomethyl)phenyl, 4-fluoro-3-amidinophenyl,4-fluoro-3-aminomethylphenyl, 4-fluoro-3-(methylaminomethyl)phenyl,6-amidinopyrid-2-yl, 6-aminomethylpyrid-2-yl, 6-aminocarbonylpyrid-2-yl,6-(methylaminomethyl)pyrid-2-yl, 6-(1-aminoethyl)pyrid-2-yl, and6-(2-amino-2-propyl)pyrid-2-yl.

[6] In another even more preferred embodiment, the present inventionprovides novel compounds of formulae Ia-Ib, wherein;

Z is C(O)CH₂ and CONH, provided that Z does not form a N—N bond withgroup A;

A is selected from phenyl, pyridyl, and pyrimidyl, and is substitutedwith 0-2 R⁴; and,

B is selected from X—Y, phenyl, pyrrolidino, morpholino,1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R^(4a);

R⁴, at each occurrence, is selected from OH, (CH₂)_(r)OR², halo, C₁₋₄alkyl, (CH₂)_(r)NR²R^(2a), and (CF₂)_(r)CF₃;

R^(4a) is selected from C₁₋₄ alkyl, CF₃, S(O)_(p)R⁵, SO₂NR²R^(2a), and1-CF₃-tetrazol-2-yl;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, andbenzyl;

X is CH₂ or C(O); and,

Y is selected from pyrrolidino and morpholino.

[7] In another further preferred embodiment, the present inventionprovides novel compounds of formulae Ia-Ib, wherein;

A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl,2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl,2-aminophenyl, and 2-methoxyphenyl; and,

B is selected from the group: 2-CF₃-phenyl, 2-(aminosulfonyl)phenyl,2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl,1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino,2-(1′-CF₃-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl,2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl,2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.

[8] In another even more preferred embodiment, the present inventionprovides novel compounds of formulae Ia-Ib, wherein;

E is phenyl substituted with R or 2-pyridyl substituted with R;

D is selected from C(O)NH₂, C(═NH)NH₂, CH₂NH₂, CH₂NHCH₃, CH(CH₃)NH₂, andC(CH₃)₂NH₂; and,

R is selected from H, OCH₃, Cl, and F;

Z is C(O)CH₂ and CONH, provided that Z does not form a N—N bond withgroup A;

A is selected from phenyl, pyridyl, and pyrimidyl, and is substitutedwith 0-2 R⁴; and,

B is selected from X—Y, phenyl, pyrrolidino, morpholino,1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R^(4a);

R⁴, at each occurrence, is selected from OH, (CH₂)_(r)OR², halo, C₁₋₄alkyl, (CH₂)_(r)NR²R^(2a), and (CF₂)_(r)CF₃;

R^(4a) is selected from C₁₋₄ alkyl, CF₃, S(O)_(p)R⁵, SO₂NR²R^(2a), and1-CF₃-tetrazol-2-yl;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, andbenzyl;

X is CH₂ or C(O); and,

Y is selected from pyrrolidino and morpholino.

[9] In another further preferred embodiment, the present inventionprovides novel compounds of formulae Ia-Ib, wherein;

D—E is selected from 3-amidinophenyl, 3-aminomethylphenyl,3-aminocarbonylphenyl, 3-(methylaminomethyl)phenyl,3-(1-aminoethyl)phenyl, 3-(2-amino-2-propyl)phenyl,4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl,4-chloro-3-(methylaminomethyl)phenyl, 4-fluoro-3-amidinophenyl,4-fluoro-3-aminomethylphenyl, 4-fluoro-3-(methylaminomethyl)phenyl,6-amidinopyrid-2-yl, 6-aminomethylpyrid-2-yl, 6-aminocarbonylpyrid-2-yl,6-(methylaminomethyl)pyrid-2-yl, 6-(1-aminoethyl)pyrid-2-yl,6-(2-amino-2-propyl)pyrid-2-yl;

A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl,2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl,2-aminophenyl, and 2-methoxyphenyl; and,

B is selected from the group: 2-CF₃-phenyl, 2-(aminosulfonyl)phenyl,2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl,1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino,2-(1′-CF₃-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl,2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl,2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.

[10] In a still further preferred embodiment, the present inventionprovides a novel compound of formula Ia.

[11] In another still further preferred embodiment, the presentinvention provides a novel compound of formula Ib.

[12] In another even more preferred embodiment, the present inventionprovides novel compounds of formulae Ia-Ib, wherein;

D is selected from C(═NR⁸)NR⁷R⁹, C(O)NR⁷R⁸, NR⁷R⁸, and CH₂NR⁷R⁸;

E is phenyl substituted with R or pyridyl substituted with R;

R is selected from H, Cl, F, OR³, CH₃, CH₂CH₃, OCF₃, and CF₃;

Z is selected from C(O), CH₂C(O), C(O)CH₂, NHC(O), and C(O)NH, providedthat Z does not form a N—N bond with group A;

R^(1a) and R^(1b) are, at each occurrence, independently selected fromH, —(CH₂)_(r)—R^(1′), NCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″),N(CH₂)₂(CH₂)_(t)R^(1′), O(CH₂)₂(CH₂)_(t)R^(1′), andS(CH₂)₂(CH₂)_(t)R^(1′);

R^(1c) is selected from H, —(CH₂)_(q)—R^(1′), C₁₋₃ alkyl, C(O)R^(2c),(CF₂)_(r)CO₂R^(2c), and C(O)NR²R^(2a);

R^(1′), at each occurrence, is selected from H, C₁₋₃ alkyl, halo,(CF₂)_(r)CF₃, OR², NR²R^(2a), C(O)R^(2c), (CF₂)_(r)CO₂R^(2c),S(O)_(p)R^(2b), NR²(CH₂)_(r)OR², NR²C(O)R^(2b), NR²C(O)₂R^(2b),C(O)NR²R^(2a), SO₂NR²R^(2a), and NR²SO₂R^(2b);

A is selected from one of the following carbocyclic and heterocyclicsystems which are substituted with 0-2 R⁴;

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl,morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl;

B is selected from: Y, X—Y, NR²R^(2a), C(═NR²)NR²R^(2a), andNR²C(═NR²)NR²R^(2a);

X is selected from CH₂, —CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—, —C(═NR)—,—CH(NR²R^(2a))—, —C(O)NR²—, —NR²C(O)—, —NR²C(O)NR²—, —NR²—, and O;

Y is NR²R^(2a), provided that X—Y do not form a N—N or O—N bond;

alternatively, Y is selected from one of the following carbocyclic andheterocyclic systems which are substituted with 0-2 R^(4a);

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl,morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl,isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,and 1,3,4-triazolyl;

R⁴, at each occurrence, is selected from ═O, OH, Cl, F, C₁₋₄ alkyl,(CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a),CH(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂-C₁₋₄ alkyl, NR²SO₂R⁵,S(O)_(p)R⁵, and (CF₂)_(r)CF₃;

R^(4a), at each occurrence, is selected from ═O, OH, Cl, F, C₁₋₄ alkyl,(CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a),CH(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂-C₁₋₄ alkyl, NR²SO₂R⁵,S(O)_(p)R⁵, (CF₂)_(r)CF₃, and 1-CF₃-tetrazol-2-yl;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenylsubstituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶;

R⁶, at each occurrence, is selected from H, ═O, OH, OR², Cl, F, CH₃, CN,NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), CH(═NH)NH₂,NHC(═NH)NH₂, and SO₂NR²R^(2a);

R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, benzyl, C₆₋₁₀ aryloxy,C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxyC₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl;

R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and benzyl; and

alternatively, R⁷ and R⁸ combine to form a morpholino group; and,

R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and benzyl.

[13] In a another further preferred embodiment, the present inventionprovides novel compounds of formulae Ia-Ib, wherein;

E is phenyl substituted with R or 2-pyridyl substituted with R;

R is selected from H, Cl, F, OCH₃, CH₃, OCF₃, and CF₃;

Z is selected from a C(O)CH₂ and C(O)NH, provided that Z does not form aN—N bond with group A;

R^(1a), at each occurrence, is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃,OCH₃, NR²R^(2a), S(O)_(p)R^(2b), CH₂S(O)_(p)R^(2b),CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c), C(O)NR²R^(2a), andSO₂NR²R^(2a);

R^(1b) is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a),S(O)_(p)R^(2b), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c),CH₂C(O)R^(2c), C(O)NR²R^(2a), and SO₂NR²R^(2a);

R^(1c) is selected from H, CH₃, CH₂CH₃, CF₃, CH₂S(O)_(p) ^(2b),CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c), and C(O)NR²R^(2a);

A is selected from one of the following carbocyclic and heterocyclicsystems which are substituted 0-2 R⁴;

phenyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl;

B is selected from: Y and X—Y;

X is selected from CH₂, —CR²(CR²R^(2b))—, —C(O)—, —C(═NR)—,—CH(NR²R^(2a))—, —C(O)NR²—, —NR²C(O)—, —NR²C(O)NR²—, —NR²—, and O;

Y is NR²R^(2a), provided that X—Y do not form a N—N or O—N bond;

alternatively, Y is selected from one of the following carbocyclic andheterocyclic systems which are substituted with 0-2 R^(4a);

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl,morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl,isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,and 1,3,4-triazolyl;

R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, CF₃, CH₃, benzyl, andphenyl;

R^(2b), at each occurrence, is selected from CF₃, OCH₃, CH₃, benzyl, andphenyl;

R^(2c), at each occurrence, is selected from CF₃, OH, OCH₃, CH₃, benzyl,and phenyl;

alternatively, R² and R^(2a) combine to form a 5 or 6 memberedsaturated, partially unsaturated, or unsaturated ring which containsfrom 0-1 additional heteroatoms selected from the group consisting of N,O, and S;

R³, at each occurrence, is selected from H, CH₃, CH₂CH₃, and phenyl;

R^(3a), at each occurrence, is selected from H, CH₃, CH₂CH₃, and phenyl;

R⁴, at each occurrence, is selected from OH, Cl, F, CH₃, CH₂CH₃,NR²R^(2a), CH₂NR²R^(2a), C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a), andCF₃;

R^(4a), at each occurrence, is selected from OH, Cl, F, CH₃, CH₂CH₃,NR²R^(2a), CH₂NR²R^(2a), C(O)R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a),S(O)_(p)R⁵, CF₃, and 1-CF₃-tetrazol-2-yl;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenylsubstituted 0-2 R⁶, and benzyl substituted with 1 R⁶;

R⁶, at each occurrence, is selected from H, OH, OCH₃, Cl, F, CH₃, CN,NO₂, NR²R^(2a), CH₂NR²R^(2a), and SO₂NR²R^(2a);

R⁷, at each occurrence, is selected from H, OH, C₁₋₃ alkyl, C₁₋₃alkylcarbonyl, C₁₋₃ alkoxy, C₁₋₄ alkoxycarbonyl, benzyl, phenoxy,phenoxycarbonyl, benzylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄alkoxycarbonyl, phenylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl;

R⁸, at each occurrence, is selected from H, CH₃, and benzyl; and,

alternatively, R⁷ and R⁸ combine to form a morpholino group;

R⁹, at each occurrence, is selected from H, CH₃, and benzyl.

[14] In a another still further preferred embodiment, the presentinvention provides novel compounds of formulae Ia-Ib, wherein;

R^(1a), at each occurrence, is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃,OCH₃, NR²R^(2a), S(O)_(p)R^(2b), C(O)NR²R^(2a), CH₂S(O)_(p)R^(2b),CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c), and SO₂NR²R^(2a);

R^(1b) is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a),S(O)_(p)R^(2b), C(O)NR²R^(2a), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b),C(O)R^(2b), CH₂C(O)R^(2b), and SO₂NR²R^(2a);

R^(1c) is selected from H, CH₃, CH₂CH₃, CF₃, C(O)NR²R^(2a),CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2b), and CH₂C(O)R^(2b);

A is selected from one of the following carbocyclic and heterocyclicsystems which are substituted 0-2 R⁴;

phenyl, pyridyl, and pyrimidyl;

B is selected from: Y and X—Y;

X is selected from —C(O)— and O;

Y is NR²R^(2a), provided that X—Y do not form a O—N bond;

alternatively, Y is selected from one of the following carbocyclic andheterocyclic systems which are substituted with 0-2 R^(4a);

phenyl, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl,imidazolyl, and 1,2,3-triazolyl;

R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, andphenyl;

R^(2a), at each occurrence, is selected from H, CF₃, CH₃, benzyl, andphenyl;

R^(2b), at each occurrence, is selected from CF₃, OCH₃, CH₃, benzyl, andphenyl;

R^(2c), at each occurrence, is selected from CF₃, OH, OCH₃, CH₃, benzyl,and phenyl;

alternatively, R² and R^(2a) combine to form a ring system selected frompyrrolidinyl, piperazinyl and morpholino;

R⁴, at each occurrence, is selected from Cl, F, CH₃, NR²R^(2a), and CF₃;

R^(4a), at each occurrence, is selected from Cl, F, CH₃, SO₂NR²R^(2a),S(O)_(p)R⁵, and CF₃; and,

R⁵, at each occurrence, is selected from CF₃ and CH₃.

[15] Specifically preferred compounds of the present invention areselected from the group:

1-(3-amidinophenyl)-5-[[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)-aminocarbonyl]-3-trifluoromethyl-pyrazoline;and,

1-(3-aminomethylphenyl)-5-[[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)-aminocarbonyl]-3-trifluoromethyl-pyrazoline;

and pharmaceutically acceptable salts thereof.

In a second embodiment, the present invention provides novelpharmaceutical compositions, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt form thereof.

In a third embodiment, the present invention provides a novel method fortreating or preventing a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt form thereof.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

When any variable (e.g., R⁶) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted 0-2 R⁶, then said groupmay optionally be substituted with up to two R⁶ groups and R⁶ at eachoccurrence is selected independently from the definition of R⁶. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “C₁₋₆ alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, examples of which include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl; “Alkenyl” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more unsaturated carbon—carbon bonds which may occur in anystable point along the chain, such as ethenyl, propenyl, and the like.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, sulfate, and thelike.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3- to 7-membered monocyclic or bicyclic or 7- to13-membered bicyclic or tricyclic, any of which may be saturated,partially unsaturated, or aromatic. Examples of such carbocyclesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” isintended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which is saturated partiallyunsaturated or unsaturated (aromatic), and which consists of carbonatoms and from 1 to 4 heteroatoms independently selected from the groupconsisting of N, O and S and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Thenitrogen and sulfur heteroatoms may optionally be oxidized. Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom which results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. If specifically noted, anitrogen in the heterocycle may optionally be quaternized. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1. As used herein, the term “aromatic heterocyclic system”is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or7- to 10-membered bicyclic heterocyclic aromatic ring which consists ofcarbon atoms and from 1 to 4 heterotams independently selected from thegroup consisting of N, O and S. It is preferred that the total number ofS and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are notlimited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl,benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl.Also included are fused ring and spiro compounds containing, forexample, the above heterocycles.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

“Prodrugs” are intended to include any covalently bonded carriers whichrelease the active parent drug according to formula (I) in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of acompound of formula (I) are prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs include compounds of formula (I) wherein a hydroxy,amino, or sulfhydryl group is bonded to any group that, when the prodrugor compound of formula (I) is administered to a mammalian subject,cleaves to form a free hydroxyl, free amino, or free sulfhydryl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds of formula (I), and the like.Preferred prodrugs are amidine prodrugs wherein D is C(═NR⁷)NH₂ or itstautomer C(═NH)NHR⁷ and R⁷ is selected from OH, C₁₋₄ alkoxy, C₆₋₁₀aryloxy, C₁₋₄ alkoxycarbonyl, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, and C₆₋₁₀arylcarbonyloxy C₁₋₄ alkoxycarbonyl. More preferred prodrugs are whereR⁷ is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, andmethylcarbonyloxymethoxycarbonyl.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

SYNTHESIS

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. It will also berecognized that another major consideration in the planning of anysynthetic route in this field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. An authoritative accountdescribing the many alternatives to the trained practitioner is Greeneand Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).All references cited herein are hereby incorporated in their entiretyherein by reference.

Pyrazolines of this invention can be easily prepared via [3+2]cycloaddition of bromo or chloro hydrazone with an appropriate acrylateaccording to the methodology described by Tewari R. S. and PariharTetrahedron 1983, 39, 129-136, or Krayushkin, M. M. et. al Izv. Akad.Nauk, Ser. Khim. 1994, 1, 114-117.

Pyrazoline 5-esters can also be prepared by the treatment of anappropriately substituted hydrazone with lead tetraacetate and anappropriate acrylate in a THF/benzene solvent system according to theprocedure of Sasaki T, et. al. Bull. Chem Soc. Jpn. 1970, 43, 1254.

Another method of obtaining pyrazoline 5-esters is the condensation ofan appropriate phenyl or heteroaryl hydrazine with an approptiate2-oxoglutaconate according to Blitzke, T. et. al. J. Prakt. Chem. 1993,335(8), 683.

Alternatively the pyrazoline ester can be prepared by treatment of adiazo-trifluoromethyl derivative with excess acrylate or acrolein in thepresence of excess pyridine (Doyle, M. O. et. al. J. Heterocyclic Chem.1983, 20, 943).

Cycloadditions as described above but with di-substituted olefins shouldresult in the formation of regio-adducts which can be easily separatedby standard chromatographic techniques.

It is understood by those in the art of organic synthesis that suchcycloadditions can also be carried out with a wide variety of electronwithdrawing olefins with functionalities such as nitro, sulfonyl,sulfonamido, nitrile, phosphate etc. These in turn can be derivatized toappropriate compounds of the present invention.

The pyrazoline carboxyesters obtained via any of the above mentionedmethodologies can be converted to the amide derivatives via the acid,acid chloride coupling methodlogies or a direct Weinreb(trimethylaluminum, aniline in dichloromethane) coupling technique knownto those in the art of organic synthesis. A variety of anilines oramines can be coupled via these methodologies to afford the desiredcompounds.

Alternatively the ester can be hydrolysed and converted to an aminofunctionality via the Curtius rearrangement. This in turn can bederivatised to obtain an amido, sulfonamido or urea derivative.

Pyrazolines wherein s is other than 0 can be prepared by alkylation ofan appropriate pyrazoline.

The electrophile can consist of simple alkyl halides to heteroaryl alkylhalides. Some of the heteroaryl alkyl groups can include pyridyl,pyrimidyl, imidazolyl etc.

In cases wherein D is a nitrile can be further converted to an amidinefunctionality via the standard Pinner-amidine reaction sequence known tothose in the art or can be converted to the benzylamine via reduction inan acidic media or can be converted to the secondary and tertiary aminevia the DIBAH/MeMgCl or MeMgBr/CeCl₃ methodologies outlined below.

Compounds wherein D is a nitro can be reduced under catalytic Pd/C/MeOHtechniques or SnCl₂/EtOAc or Zn/AcOH conditions to afford the desiredamino derivatives.

Enantiomers of the pyrazolines can be easily obtained either via lipasehydrolysis of its esters or resolution with common chiral bases known tothose in the art.

1,2,3-Triazolines can be synthesized via the cycloaddition methodologyhowever in this case the dipole is an aryl azide and the dipolarophileis a variety of olefins bearing an electron withdrawing group such as anester, amide or sulfonamide.

1,2,4-Triazolines can be prepared via the methods of Sandhy J. S. et.al. Heterocycles 1985, 23(5), 1143, and Heterocycles 1985, 23(5), 1123,by the method described in the scheme below.

The triazoline esters can then subjected to the standard couplingprocedures discussed above to afford the desired amide analogs. Thesecan then further modified to the prepare compounds of the presentinvention.

Compounds of the present invention wherein AB is a biphenylamine orsimilar amine may be prepared as shown in the following scheme.4-Bromoaniline can be protected as Boc-derivative and coupled to aphenylboronic acid under Suzuki conditions (Bioorg. Med. Chem. Lett.1994, 189). Deprotection with TFA provides the aminobiphenyl compound.Other similar amines wherein A and/or B are heterocycles can be preparedby the same method using appropiately substituted boronic acids andarylbromide. The bromoaniline can also be linked to the core ringstructures first as described above, and then undergo a Suzuki reactionto give the desired product.

Compounds of the present invention wherein A—B is A—X—Y can be preparedlike the piperazine derivative :3shown below.

The following scheme shows how one can couple cyclic groups whereinX═NH, O, or S.

When B is defined as X—Y, the following description applies. Groups Aand B are available either through commercial sources, known in theliterature or readily synthesized by the adaptation of standardprocedures known to practioners skilled in the art of organic synthesis.The required reactive functional groups appended to analogs of A and Bare also available either through commercial sources, known in theliterature or readily synthesized by the adaptation of standardprocedures known to practioners skilled in the art of organic synthesis.In the tables that follow the chemistry required to effect the couplingof A to B is outlined.

TABLE A Preparation of Amide, Ester, Urea, Sulfonamide and Sulfamidelinkages between A and B. then the reactive to give the Rxn. substituentof following product No. if A contains: Y is: A—X—Y: 1 A—NHR² as aClC(O)—Y A—NR²—C(O)—Y substituent 2 a secondary NH ClC(O)—Y A—C(O)—Y aspart of a ring or chain 3 A—OH as a ClC(O)—Y A—O—C(O)—Y substituent 4A—NHR² as a ClC(O)—CR²R^(2a)—Y A—NR²—C(O)—CR²R^(2a)—Y substituent 5 asecondary NH ClC(O)—CR²R^(2a)—Y A—C(O)—CR²R^(2a)—Y as part of a ring orchain 6 A—OH as a ClC(O)—CR²R^(2a)—Y A—O—C(O)CR²R^(2a)—Y substituent 7A—NHR³ as a ClC(O)NR²—Y A—NR²—C(O)NR²—Y substituent 8 a secondary NHClC(O)NR²—Y A—C(O)NR²—Y as part of a ring or chain 9 A—OH as aClC(O)NR²—Y A—Q—C(O)NR²—Y substituent 10 A—NHR² as a ClSO₂—Y A—NR²—SO₂—Ysubstituent 11 a secondary NH ClSO₂—Y A—SO₂—Y as part of a ring or chain12 A—NHR² as a ClSO₂—CR²R^(2a)—Y A—NR²—SO₂—CR²R^(2a)—Y substituent 13 asecondary NH ClSO₂—CR²R^(2a)—Y A—SO₂—CR²R^(2a)—Y as part of a ring orchain 14 A—NHR² as a ClSO₂—NR²—Y A—NR²—SO₂—NR²—Y substituent 15 asecondary NH ClSO₂—NR²—Y A—SO₂—NR²—Y as part of a ring or chain 16A—C(O)Cl HO—Y as a A—C(O)—O—Y substituent 17 A—C(O)Cl NHR²—Y as aA—C(O)—NR²—Y substituent 18 A—C(O)Cl a secondary NH A—C(O)—Y as part ofa ring or chain 19 A—CR²R^(2a)C(O)Cl HO—Y as a A—CR²R^(2a)C(O)—O—Ysubstituent 20 A—CR²R^(2a)C(O)Cl NHR²—Y as a A—CR²R^(2a)C(O)—NR²—Ysubstituent 21 A—CR²R^(2a)C(O)Cl a secondary NH A—CR²R^(2a)C(O)—Y aspart ot a ring or chain 22 A—SO₂Cl NHR²—Y as a A—SO₂—NR²—Y substituent23 A—SO₂Cl a secondary NH A—SO₂—Y as part of a ring or chain 24A—CR²R^(2a)SO₂Cl NHR²—Y as a A—CR²R^(2a)SO₂—NR²—Y substituent 25A—CR²R^(2a)SO₂Cl a secondary NH A—CR²R^(2a)SO₂—Y as part of a ring orchain

The chemistry of Table A can be carried out in aprotic solvents such asa chlorocarbon, pyridine, benzene or toluene, at temperatures rangingfrom −20° C. to the reflux point of the solvent and with or without atrialkylamine base.

TABLE B Preparation of ketone linkages between A and B. then thereactive to give the Rxn. substituent of following product No. if Acontains: Y is: A—X—Y: 1 A—C(O)Cl BrMg—Y A—C(O)—Y 2 A—CR²R^(2a)C(O)ClBrMg—Y A—CR²R^(2a) ₂C(O)—Y 3 A—C(O)Cl BrMgCR²R^(2a)—Y A—C(O)CR²R^(2a)—Y4 A—CR²R^(2a)C(O)Cl BrMgCR²R^(2a)—Y A—CR²R^(2a)C(O)CR²R^(2a)— Y

The coupling chemistry of Table B can be (carried out by a variety ofmethods. The Grignard reagent required for Y is prepared from a halogenanalog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0° C. tothe reflux point of the solvent. This Grignard reagent can be reacteddirectly under very controlled conditions, that is low temeprature (−20°C. or lower) and with a large excess of acid chloride or with catalyticor stoichiometric copper bromide.dimethyl sulfide complex in dimethylsulfide as a solvent or with a variant thereof. Other methods availableinclude transforming the Grignard reagent to the cadmium reagent andcoupling according to the procedure of Carson and Prout (Org. Syn. Col.Vol. 3 (1955) 601) or a coupling mediated by Fe(acac)₃ according toFiandanese et al. (Tetrahedron Lett., (1984) 4805), or a couplingmediated by manganese (II) catalysis (Cahiez and Laboue, TetrahedronLett., 33(31), (1992) 4437).

TABLE C Preparation of ether and thioether linkages between A and B thenthe reactive to give the Rxn. substituent of following No. if Acontains: Y is: product A—X—Y: 1 A—OH Br—Y A—O—Y 2 A—CR²R^(2a)—OH Br—YA—CR²R^(2a)—Y 3 A—OH Br—CR²R^(2a)—Y A—OCR²R^(2a)—Y 4 A—SH Br—Y A—S—Y 5A—CR²R^(2a)—SH Br—Y A—CR²R^(2a)S—Y 6 A—SH Br—CR²R^(2a)—Y A—SCR²R^(2a)—Y

The ether and thioether linkages of Table C can be prepared by reactingthe two components in a polar aprotic solvent such as acetone,dimethylformamide or dimethylsulfoxide in the presence of a base such aspotassium carbonate, sodium hydride or potassium t-butoxide attemperature ranging from ambient temperature to the reflux point of thesolvent used.

TABLE D Preparation of —SO— and —SO₂— linkages from thioethers of Table3. and it is oxidized and it is oxidized with m-chloroper- with Alumina(wet)/ benzoic acid (Satoh if the Oxone (Greenhalgh, et al., Chem. Lett.Rxn. starting Synlett, (1992) 235) (1992) 381), the No. material is: theproduct is: product is: 1 A—S—Y A—S(O)—Y A—SO₂—Y 2 A—CR²R^(2a)S—YA—CR²R^(2a)S(O)—Y A—CR²R^(2a)SO₂—Y 3 A—SCR²R^(2a)—Y A—S(O)CR²R^(2a)—YA—SO₂CR²R^(2a)—Y

The thioethers of Table C serve as a convenient starting material forthe preparation of the sulfoxide and sulfone analogs of Table D. Acombination of wet alumina and oxone can provide a reliable reagent forthe oxidation of the thioether to the sulfoxide while m-chloroperbenzoicacid oxidation will give the sulfone.

TABLE E Methods of Preparing Group E Rxn Q D is to be then atransformation that may be used is: 1 —CN —C(═NH)NH2

2 —CN —CH2NH2

3 —CO2H —CH2NH2

4 —CO2H —NH2

In Table E several methods of transforming a functional group Q intogroup D of Formula 1 are shown. While not all possible functional groupsfor Q and D are listed and the synthetic methods suggested are notcomprehensive, Table E is meant to illustrate strategies andtransformations available to a practitioner skilled in the art oforganic synthesis for preparing compounds of Formula 1. In reaction 1 ofTable E the transformation of a nitrile into an amidine by the Pinnermethodology is shown; in reaction 2 the direct reduction of a nitrile bya hydride reducing agent to a methylene amine is illustrated. Inreaction 3, the utility of a carboxylic acid, which may be readilyderived from its ester or a nitrile if necessary, in the preparation ofa methylene amine is shown. This synthetic route is exceptionallyflexible because of the several stable intermediates prepared en routeto the final product. As outlined, formation of an activated analog,such as the mixed anhydride, allows for the mild reduction of the acidto the methylene alcohol, this may in turn be transformed into a leavinggroup by sulfonylation or halogenation or protected with a suitableprotecting group to be transformed later in the synthesis as thechemistry demands. Once the methylene alcohol is so activated,displacement by an efficient nitrogen nucleophile, such as azide anion,can again provide another suitably stable analog,—the methyleneazide—which may be used as a protected form of the methylene amine ortransformed directly into the methylene amine group by reduction.Reaction 4 addresses the problem of appending the amine functionalitydirectly through a bond to group E of Formula 1. Once again, thecarboxylic acid provides a convenient entre into this selection forgroup D. The well-know Curtius rearrangement is illustrated here; anactivated acid analog can be used to form an acyl azide which uponthermal decomposition is rearranged to the corresponding isocyanate. Theisocyanate intermediate may then be captured as a stable carbamate bythe addition of a suitable alcohol and further heating. This carbamatecan be used as a stable protecting group for the amine or cleaveddirectly to the desired D. Alternatively, it may be convenient to quenchthe isocyanate intermediate with water to give the amine directly.

One diastereomer of a compound of Formula I may display superioractivity compared with the others. Thus, the following stereochemistriesare considered to be a part of the present invention.

When required, separation of the racemic material can be achieved byHPLC using a chiral column or by a resolution using a resolving agentsuch as camphonic chloride as in Steven D. Young, et al, AntimicrobialAgents and Chemotheraphy, 1995, 2602-2605. A chiral compound of FormulaI may also be directly synthesized using a chiral catalyst or a chiralligand, e.g., Andrew S. Thompson, et al, Tet. lett. 1995, 36,8937-8940).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES Examples 1 and 21-(3-Amidinophenyl)-5-[[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)-aminocarbonyl]-3-trifluoromethyl-pyrazolineand1-(3-aminomethylphenyl)-5-[[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)-aminocarbonyl]-3-trifluoromethyl-pyrazoline

Part A: To a methanolic solution containing meta-cyanophenyl-hydrazine(2 g, 15.03 mmol) was added trifluoromethylacetaldehyde hydrate (1.74 g,15.03 mmol). The reaction mixture was heated to gentle reflux overnight.Methanol was stripped off to afford yellow crystals of pure hydrazone(2.99 g, 93%). ¹HNMR (CDCl₃) δ: 10.10 (bs, 1H), 7.33 (m, 2H), 7.10 (m,2H) ppm; ESI (−ve) mass spectrum analysis m/z (relative intensity) 212(M−H, 100).

Part B: NCS (1.02 g, 7.69 mmol) was added to a DMF (25 mL) solution ofthe compound prepared in part A (1.64 g, 7.69 mmol). The reactionmixture was stirred at room temperature over night, quenched with water(500 mL) and organics extracted with ethyl acetate (2×100 mL) dried(MgSO₄) and evaporated to a reddish brown oil. The oil was redissolvedin chloroform (25 mL) and to this solution was addled ethyl acrylate (10mL) followed by slow addition of triethylamine (0.81 mL, 5.75 mmoL). Thereaction mixture was refluxed for 18 h cooled and quenched with dil.hydrochloric acid (1N, 20 mL). The organic layer was separated andevaporated to an oil. Chromatography on silica gel (7:3,Hexane:ethylacetate) afforded a colorless oil which solidified onstanding (1.5 g, 62%). ¹HNMR(CDCl₃) δ: 7.40-7.22 (m, 4H), 4.89 (dd,J=6.2 and 13.4 Hz, 1H), 4.24 (q, 2H), 3.63-3.50 (dd, J=1.9 and 13.2 Hz,1H), 3.38 (dd, J=1.9 and 14 Hz, 1H), 1.23 (t, 3H) ppm; ESI mass spectrumanalysis m/z (relative intensity) 312 (M+H, 100).

Part C: The product from part B was treated with2′-methylsulfonyl-4-amino-[1,1′]biphenyl under Weinreb conditions(trimethylaluminum in dichloromethane) to afford pure coupled product(oil) after silica gel column chromatography (hexane:ethyl acetate 7:3).¹HNMR(CDCl₃) δ: 8.40 (bs, 1H), 8.17 (dd, J=1.1 and 7.8 Hz, 1H),7.65-7.25 (m, 1H), 4.90 (m, 1H), 3.78 (m, 1H), 3.38 (dd, J=1.5 and 8.1Hz, 1H), 2.69 s, 3H); ESI (−ve) mass spectrum analysis m/z (rel.intensity) 511 (M−H, 100).

Part D: The product from part C was subjected to the Pinner amidinereaction sequence (HCl/MeOH followed by ammonium carbonate in methanol),purified via standard HPLC purification, lyophilization to afford (40%yield) of Example 1 as colorless crystals. ¹HNMR(DMSO₆) δ: 9.36 (bs,1.5H), 9.00 (bs, 1.5 Hz), 8.06 (d, J=7.7 Hz, 1H), 7.53-7.78 (m, 6H),7.35 (d, J=8.1 Hz, 3H), 7.27 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H),5.33 (dd, J=6.2 and 13.2 Hz, 1H), 3.76 (t, 1H), 3.40 (d, J=3.1 Hz, 1H),2.84(s, 3H) ppm; ESI (+ve) mass spectum analysis m/z (relativeintensity) 530 (M+H, 100).

Additionally, the compound form Part C was subjected to reduction using10% Pd/C in an acidic medium (methanol/acetic acid). Purification viastandard HPLC techniques and lyophilization afforded the benzylamine(10% yield). ¹HNMR(DMSO₆) δ: 8.07 (bs, 2H), 8.01 (d, J=8 Hz, 1H), 7.70(m, 1H), 7.59 (m, 3H), 7.28 (m, 4H), 6.95 (d, J=8 Hz, 1H), 6.83 (dd,J=1/5 and 8 Hz, 1H), 6.40 (bs, 2H), 5.22 (dd, J=6.5 and 13 Hz, 1H), 4.00(m, 1H), 3.71 (m, 1H), 3.34 (dd, J=1.5 and 8 Hz, 1H), 2.84 (s, 3H) ppm;ESI mass spectrum analysis m/z (relative intensity) 517 (M+H, 100).

The following tables contain representative examples of the presentinvention. Each entry in each table is intended to be paired with eachformulae at the start of the table. For example, in Table 1, example 1is intended to be paired with each of formulae a-ttt and in Table 2,example 1 is intended to be paired with each of formulae a-ss.

The following groups are intended for group A in the following tables.

TABLE 1

Ex # R^(1c) A B  1 CH₃ phenyl 2-(aminosulfonyl)phenyl  2 CH₃ phenyl2-(methylaminosulfonyl)phenyl  3 CH₃ phenyl 1-pyrrolidinocarbonyl  4 CH₃phenyl 2-(methylsulfonyl)phenyl  5 CH₃ phenyl 4-morpholino  6 CH₃ phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl  7 CH₃ phenyl 4-morpholinocarbonyl  8 CH₃phenyl 2-methyl-1-imidazolyl  9 CH₃ phenyl 5-methyl-1-imidazolyl  10 CH₃phenyl 2-methylsulfonyl-1-imidazolyl  11 CH₃ 2-pyridyl2-(aminosulfonyl)phenyl  12 CH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 13 CH₃ 2-pyridyl 1-pyrrolidinocarbonyl  14 CH₃ 2-pyridyl2-(methylsulfonyl)phenyl  15 CH₃ 2-pyridyl 4-morpholino  16 CH₃2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl  17 CH₃ 2-pyridyl4-morpholinocarbonyl  18 CH₃ 2-pyridyl 2-methyl-1-imidazolyl  19 CH₃2-pyridyl 5-methyl-1-imidazolyl  20 CH₃ 2-pyridyl2-methylsulfonyl-1-imidazolyl  21 CH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 22 CH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl  23 CH₃ 3-pyridyl1-pyrrolidinocarbonyl  24 CH₃ 3-pyridyl 2-(methylsulfonyl)phenyl  25 CH₃3-pyridyl 4-morpholino  26 CH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 27 CH₃ 3-pyridyl 4-morpholinocarbonyl  28 CH₃ 3-pyridyl2-methyl-1-imidazolyl  29 CH₃ 3-pyridyl 5-methyl-1-imidazolyl  30 CH₃3-pyridyl 2-methylsulfonyl-1-imidazolyl  31 CH₃ 2-pyrimidyl2-(aminosulfonyl)phenyl  32 CH₃ 2-pyrimidyl2-(methylaminosulfonyl)phenyl  33 CH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 34 CH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl  35 CH₃ 2-pyrimidyl4-morpholino  36 CH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl  37 CH₃2-pyrimidyl 4-morpholinocarbonyl  38 CH₃ 2-pyrimidyl2-methyl-1-imidazolyl  39 CH₃ 2-pyrimidyl 5-methyl-1-imidazolyl  40 CH₃2-pyrimidyl 2-methylsulfonyl-1-imidazolyl  41 CH₃ 5-pyrimidyl2-(aminosulfonyl)phenyl  42 CH₃ 5-pyrimidyl2-(methylaminosulfonyl)phenyl  43 CH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 44 CH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl  45 CH₃ 5-pyrimidyl4-morpholino  46 CH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl  47 CH₃5-pyrimidyl 4-morpholinocarbonyl  48 CH₃ 5-pyrimidyl2-methyl-1-imidazolyl  49 CH₃ 5-pyrimidyl 5-methyl-1-imidazolyl  50 CH₃5-pyrimidyl 2-methylsulfonyl-1-imidazolyl  51 CH₃ 2-Cl-phenyl2-(aminosulfonyl)phenyl  52 CH₃ 2-Cl-phenyl2-(methylaminosulfonyl)phenyl  53 CH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 54 CH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl  55 CH₃ 2-Cl-phenyl4-morpholino  56 CH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl  57 CH₃2-Cl-phenyl 4-morpholinocarbonyl  58 CH₃ 2-Cl-phenyl2-methyl-1-imidazolyl  59 CH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl  60 CH₃2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl  61 CH₃ 2-F-phenyl2-(aminosulfonyl)phenyl  62 CH₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 63 CH₃ 2-F-phenyl 1-pyrrolidinocarbonyl  64 CH₃ 2-F-phenyl2-(methylsulfonyl)phenyl  65 CH₃ 2-F-phenyl 4-morpholino  66 CH₃2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl  67 CH₃ 2-F-phenyl4-morpholinocarbonyl  68 CH₃ 2-F-phenyl 2-methyl-1-imidazolyl  69 CH₃2-F-phenyl 5-methyl-1-imidazolyl  70 CH₃ 2-F-phenyl2-methylsulfonyl-1-imidazolyl  71 CH₃ 2,6-diF-phenyl2-(aminosulfonyl)phenyl  72 CH₃ 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl  73 CH₃ 2,6-diF-phenyl1-pyrrolidinocarbonyl  74 CH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 75 CH₃ 2,6-diF-phenyl 4-morpholino  76 CH₃ 2,6-diF-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl  77 CH₃ 2,6-diF-phenyl4-morpholinocarbonyl  78 CH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl  79CH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl  80 CH₃ 2,6-diF-phenyl2-methylsulfonyl-1-imidazolyl  81 CH₂CH₃ phenyl 2-(aminosulfonyl)phenyl 82 CH₂CH₃ phenyl 2-(methylaminosulfonyl)phenyl  83 CH₂CH₃ phenyl1-pyrrolidinocarbonyl  84 CH₂CH₃ phenyl 2-(methylsulfonyl)phenyl  85CH₂CH₃ phenyl 4-morpholino  86 CH₂CH₃ phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl  87 CH₂CH₃ phenyl 4-morpholinocarbonyl 88 CH₂CH₃ phenyl 2-methyl-1-imidazolyl  89 CH₂CH₃ phenyl5-methyl-1-imidazolyl  90 CH₂CH₃ phenyl 2-methylsulfonyl-1-imidazolyl 91 CH₂CH₃ 2-pyridyl 2-(aminosulfonyl)phenyl  92 CH₂CH₃ 2-pyridyl2-(methylaminosulfonyl)phenyl  93 CH₂CH₃ 2-pyridyl 1-pyrrolidinocarbonyl 94 CH₂CH₃ 2-pyridyl 2-(methylsulfonyl)phenyl  95 CH₂CH₃ 2-pyridyl4-morpholino  96 CH₂CH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl  97CH₂CH₃ 2-pyridyl 4-morpholinocarbonyl  98 CH₂CH₃ 2-pyridyl2-methyl-1-imidazolyl  99 CH₂CH₃ 2-pyridyl 5-methyl-1-imidazolyl 100CH₂CH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 101 CH₂CH₃ 3-pyridyl2-(aminosulfonyl)phenyl 102 CH₂CH₃ 3-pyridyl2-(methylaminosulfonyl)phenyl 103 CH₂CH₃ 3-pyridyl 1-pyrrolidinocarbonyl104 CH₂CH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 105 CH₂CH₃ 3-pyridyl4-morpholino 106 CH₂CH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 107CH₂CH₃ 3-pyridyl 4-morpholinocarbonyl 108 CH₂CH₃ 3-pyridyl2-methyl-1-imidazolyl 109 CH₂CH₃ 3-pyridyl 5-methyl-1-imidazolyl 110CH₂CH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 111 CH₂CH₃ 2-pyrimidyl2-(aminosulfonyl)phenyl 112 CH₂CH₃ 2-pyrimidyl2-(methylaminosulfonyl)phenyl 113 CH₂CH₃ 2-pyrimidyl1-pyrrolidinocarbonyl 114 CH₂CH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl115 CH₂CH₃ 2-pyrimidyl 4-morpholino 116 CH₂CH₃ 2-pyrimidyl2-(1′-CF₃-tetrazol-2-yl)phenyl 117 CH₂CH₃ 2-pyrimidyl4-morpholinocarbonyl 118 CH₂CH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 119CH₂CH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 120 CH₂CH₃ 2-pyrimidyl2-methylsulfonyl-1-imidazolyl 121 CH₂CH₃ 5-pyrimidyl2-(aminosulfonyl)phenyl 122 CH₂CH₃ 5-pyrimidyl2-(methylaminosulfonyl)phenyl 123 CH₂CH₃ 5-pyrimidyl1-pyrrolidinocarbonyl 124 CH₂CH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl125 CH₂CH₃ 5-pyrimidyl 4-morpholino 126 CH₂CH₃ 5-pyrimidyl2-(1′-CF₃-tetrazol-2-yl)phenyl 127 CH₂CH₃ 5-pyrimidyl4-morpholinocarbonyl 128 CH₂CH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 129CH₂CH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 130 CH₂CH₃ 5-pyrimidyl2-methylsulfonyl-1-imidazolyl 131 CH₂CH₃ 2-Cl-phenyl2-(aminosulfonyl)phenyl 132 CH₂CH₃ 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 133 CH₂CH₃ 2-Cl-phenyl1-pyrrolidinocarbonyl 134 CH₂CH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl135 CH₂CH₃ 2-Cl-phenyl 4-morpholino 136 CH₂CH₃ 2-Cl-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 137 CH₂CH₃ 2-Cl-phenyl4-morpholinocarbonyl 138 CH₂CH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 139CH₂CH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 140 CH₂CH₃ 2-Cl-phenyl2-methylsulfonyl-1-imidazolyl 141 CH₂CH₃ 2-F-phenyl2-(aminosulfonyl)phenyl 142 CH₂CH₃ 2-F-phenyl2-(methylaminosulfonyl)phenyl 143 CH₂CH₃ 2-F-phenyl1-pyrrolidinocarbonyl 144 CH₂CH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 145CH₂CH₃ 2-F-phenyl 4-morpholino 146 CH₂CH₃ 2-F-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 147 CH₂CH₃ 2-F-phenyl4-morpholinocarbonyl 148 CH₂CH₃ 2-F-phenyl 2-methyl-1-imidazolyl 149CH₂CH₃ 2-F-phenyl 5-methyl-1-imidazolyl 150 CH₂CH₃ 2-F-phenyl2-methylsulfonyl-1-imidazolyl 151 CH₂CH₃ 2,6-diF-phenyl2-(aminosulfonyl)phenyl 152 CH₂CH₃ 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 153 CH₂CH₃ 2,6-diF-phenyl1-pyrrolidinocarbonyl 154 CH₂CH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl155 CH₂CH₃ 2,6-diF-phenyl 4-morpholino 156 CH₂CH₃ 2,6-diF-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 157 CH₂CH₃ 2,6-diF-phenyl4-morpholinocarbonyl 158 CH₂CH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 159CH₂CH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 160 CH₂CH₃ 2,6-diF-phenyl2-methylsulfonyl-1-imidazolyl 161 CF₃ phenyl 2-(aminosulfonyl)phenyl 162CF₃ phenyl 2-(methylaminosulfonyl)phenyl 163 CF₃ phenyl1-pyrrolidinocarbonyl 164 CF₃ phenyl 2-(methylsulfonyl)phenyl 165 CF₃phenyl 4-morpholino 166 CF₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 167CF₃ phenyl 4-morpholinocarbonyl 168 CF₃ phenyl 2-methyl-1-imidazolyl 169CF₃ phenyl 5-methyl-1-imidazolyl 170 CF₃ phenyl2-methylsulfonyl-1-imidazolyl 171 CF₃ 2-pyridyl 2-(aminosulfonyl)phenyl172 CF₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 173 CF₃ 2-pyridyl1-pyrrolidinocarbonyl 174 CF₃ 2-pyridyl 2-(methylsulfonyl)phenyl 175 CF₃2-pyridyl 4-morpholino 176 CF₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl177 CF₃ 2-pyridyl 4-morpholinocarbonyl 178 CF₃ 2-pyridyl2-methyl-1-imidazolyl 179 CF₃ 2-pyridyl 5-methyl-1-imidazolyl 180 CF₃2-pyridyl 2-methylsulfonyl-1-imidazolyl 181 CF₃ 3-pyridyl2-(aminosulfonyl)phenyl 182 CF₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl183 CF₃ 3-pyridyl 1-pyrrolidinocarbonyl 184 CF₃ 3-pyridyl2-(methylsulfonyl)phenyl 185 CF₃ 3-pyridyl 4-morpholino 186 CF₃3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 187 CF₃ 3-pyridyl4-morpholinocarbonyl 188 CF₃ 3-pyridyl 2-methyl-1-imidazolyl 189 CF₃3-pyridyl 5-methyl-1-imidazolyl 190 CF₃ 3-pyridyl2-methylsulfonyl-1-imidazolyl 191 CF₃ 2-pyrimidyl2-(aminosulfonyl)phenyl 192 CF₃ 2-pyrimidyl2-(methylaminosulfonyl)phenyl 193 CF₃ 2-pyrimidyl 1-pyrrolidinocarbonyl194 CF₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 195 CF₃ 2-pyrimidyl4-morpholino 196 CF₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 197 CF₃2-pyrimidyl 4-morpholinocarbonyl 198 CF₃ 2-pyrimidyl2-methyl-1-imidazolyl 199 CF₃ 2-pyrimidyl 5-methyl-1-imidazolyl 200 CF₃2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 201 CF₃ 5-pyrimidyl2-(aminosulfonyl)phenyl 202 CF₃ 5-pyrimidyl2-(methylaminosulfonyl)phenyl 203 CF₃ 5-pyrimidyl 1-pyrrolidinocarbonyl204 CF₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 205 CF₃ 5-pyrimidyl4-morpholino 206 CF₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 207 CF₃5-pyrimidyl 4-morpholinocarbonyl 208 CF₃ 5-pyrimidyl2-methyl-1-imidazolyl 209 CF₃ 5-pyrimidyl 5-methyl-1-imidazolyl 210 CF₃5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 211 CF₃ 2-Cl-phenyl2-(aminosulfonyl)phenyl 212 CF₃ 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 213 CF₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl214 CF₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 215 CF₃ 2-Cl-phenyl4-morpholino 216 CF₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 217 CF₃2-Cl-phenyl 4-morpholinocarbonyl 218 CF₃ 2-Cl-phenyl2-methyl-1-imidazolyl 219 CF₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 220 CF₃2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 221 CF₃ 2-F-phenyl2-(aminosulfonyl)phenyl 222 CF₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl223 CF₃ 2-F-phenyl 1-pyrrolidinocarbonyl 224 CF₃ 2-F-phenyl2-(methylsulfonyl)phenyl 225 CF₃ 2-F-phenyl 4-morpholino 226 CF₃2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 227 CF₃ 2-F-phenyl4-morpholinocarbonyl 228 CF₃ 2-F-phenyl 2-methyl-1-imidazolyl 229 CF₃2-F-phenyl 5-methyl-1-imidazolyl 230 CF₃ 2-F-phenyl2-methylsulfonyl-1-imidazolyl 231 CF₃ 2,6-diF-phenyl2-(aminosulfonyl)phenyl 232 CF₃ 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 233 CF₃ 2,6-diF-phenyl1-pyrrolidinocarbonyl 234 CF₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl235 CF₃ 2,6-diF-phenyl 4-morpholino 236 CF₃ 2,6-diF-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 237 CF₃ 2,6-diF-phenyl4-morpholinocarbonyl 238 CF₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 239CF₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 240 CF₃ 2,6-diF-phenyl2-methylsulfonyl-1-imidazolyl 241 SCH₃ phenyl 2-(aminosulfonyl)phenyl242 SCH₃ phenyl 2-(methylaminosulfonyl)phenyl 243 SCH₃ phenyl1-pyrrolidinocarbonyl 244 SCH₃ phenyl 2-(methylsulfonyl)phenyl 245 SCH₃phenyl 4-morpholino 246 SCH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 247SCH₃ phenyl 4-morpholinocarbonyl 248 SCH₃ phenyl 2-methyl-1-imidazolyl249 SCH₃ phenyl 5-methyl-1-imidazolyl 250 SCH₃ phenyl2-methylsulfonyl-1-imidazolyl 251 SCH₃ 2-pyridyl 2-(aminosulfonyl)phenyl252 SCH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 253 SCH₃ 2-pyridyl1-pyrrolidinocarbonyl 254 SCH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 255SCH₃ 2-pyridyl 4-morpholino 256 SCH₃ 2-pyridyl2-(1′-CF₃-tetrazol-2-yl)phenyl 257 SCH₃ 2-pyridyl 4-morpholinocarbonyl258 SCH₃ 2-pyridyl 2-methyl-1-imidazolyl 259 SCH₃ 2-pyridyl5-methyl-1-imidazolyl 260 SCH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl261 SCH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 262 SCH₃ 3-pyridyl2-(methylaminosulfonyl)phenyl 263 SCH₃ 3-pyridyl 1-pyrrolidinocarbonyl264 SCH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 265 SCH₃ 3-pyridyl4-morpholino 266 SCH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 267 SCH₃3-pyridyl 4-morpholinocarbonyl 268 SCH₃ 3-pyridyl 2-methyl-1-imidazolyl269 SCH₃ 3-pyridyl 5-methyl-1-imidazolyl 270 SCH₃ 3-pyridyl2-methylsulfonyl-1-imidazolyl 271 SCH₃ 2-pyrimidyl2-(aminosulfonyl)phenyl 272 SCH₃ 2-pyrimidyl2-(methylaminosulfonyl)phenyl 273 SCH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl274 SCH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 275 SCH₃ 2-pyrimidyl4-morpholino 276 SCH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 277SCH₃ 2-pyrimidyl 4-morpholinocarbonyl 278 SCH₃ 2-pyrimidyl2-methyl-1-imidazolyl 279 SCH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 280SCH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 281 SCH₃ 5-pyrimidyl2-(aminosulfonyl)phenyl 282 SCH₃ 5-pyrimidyl2-(methylaminosulfonyl)phenyl 283 SCH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl284 SCH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 285 SCH₃ 5-pyrimidyl4-morpholino 286 SCH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 287SCH₃ 5-pyrimidyl 4-morpholinocarbonyl 288 SCH₃ 5-pyrimidyl2-methyl-1-imidazolyl 289 SCH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 290SCH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 291 SCH₃ 2-Cl-phenyl2-(aminosulfonyl)phenyl 292 SCH₃ 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 293 SCH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl294 SCH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 295 SCH₃ 2-Cl-phenyl4-morpholino 296 SCH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 297SCH₃ 2-Cl-phenyl 4-morpholinocarbonyl 298 SCH₃ 2-Cl-phenyl2-methyl-1-imidazolyl 299 SCH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 300SCH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 301 SCH₃ 2-F-phenyl2-(aminosulfonyl)phenyl 302 SCH₃ 2-F-phenyl2-(methylaminosulfonyl)phenyl 303 SCH₃ 2-F-phenyl 1-pyrrolidinocarbonyl304 SCH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 305 SCH₃ 2-F-phenyl4-morpholino 306 SCH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 307 SCH₃2-F-phenyl 4-morpholinocarbonyl 308 SCH₃ 2-F-phenyl2-methyl-1-imidazolyl 309 SCH₃ 2-F-phenyl 5-methyl-1-imidazolyl 310 SCH₃2-F-phenyl 2-methylsulfonyl-1-imidazolyl 311 SCH₃ 2,6-diF-phenyl2-(aminosulfonyl)phenyl 312 SCH₃ 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 313 SCH₃ 2,6-diF-phenyl1-pyrrolidinocarbonyl 314 SCH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl315 SCH₃ 2,6-diF-phenyl 4-morpholino 316 SCH₃ 2,6-diF-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 317 SCH₃ 2,6-diF-phenyl4-morpholinocarbonyl 318 SCH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 319SCH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 320 SCH₃ 2,6-diF-phenyl2-methylsulfonyl-1-imidazolyl 321 SOCH₃ phenyl 2-(aminosulfonyl)phenyl322 SOCH₃ phenyl 2-(methylaminosulfonyl)phenyl 323 SOCH₃ phenyl1-pyrrolidinocarbonyl 324 SOCH₃ phenyl 2-(methylsulfonyl)phenyl 325SOCH₃ phenyl 4-morpholino 326 SOCH₃ phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 327 SOCH₃ phenyl 4-morpholinocarbonyl 328SOCH₃ phenyl 2-methyl-1-imidazolyl 329 SOCH₃ phenyl5-methyl-1-imidazolyl 330 SOCH₃ phenyl 2-methylsulfonyl-1-imidazolyl 331SOCH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 332 SOCH₃ 2-pyridyl2-(methylaminosulfonyl)phenyl 333 SOCH₃ 2-pyridyl 1-pyrrolidinocarbonyl334 SOCH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 335 SOCH₃ 2-pyridyl4-morpholino 336 SOCH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 337SOCH₃ 2-pyridyl 4-morpholinocarbonyl 338 SOCH₃ 2-pyridyl2-methyl-1-imidazolyl 339 SOCH₃ 2-pyridyl 5-methyl-1-imidazolyl 340SOCH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 341 SOCH₃ 3-pyridyl2-(aminosulfonyl)phenyl 342 SOCH₃ 3-pyridyl2-(methylaminosulfonyl)phenyl 343 SOCH₃ 3-pyridyl 1-pyrrolidinocarbonyl344 SOCH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 345 SOCH₃ 3-pyridyl4-morpholino 346 SOCH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 347SOCH₃ 3-pyridyl 4-morpholinocarbonyl 348 SOCH₃ 3-pyridyl2-methyl-1-imidazolyl 349 SOCH₃ 3-pyridyl 5-methyl-1-imidazolyl 350SOCH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 351 SOCH₃ 2-pyrimidyl2-(aminosulfonyl)phenyl 352 SOCH₃ 2-pyrimidyl2-(methylaminosulfonyl)phenyl 353 SOCH₃ 2-pyrimidyl1-pyrrolidinocarbonyl 354 SOCH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 355SOCH₃ 2-pyrimidyl 4-morpholino 356 SOCH₃ 2-pyrimidyl2-(1′-CF₃-tetrazol-2-yl)phenyl 357 SOCH₃ 2-pyrimidyl4-morpholinocarbonyl 358 SOCH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 359SOCH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 360 SOCH₃ 2-pyrimidyl2-methylsulfonyl-1-imidazolyl 361 SOCH₃ 5-pyrimidyl2-(aminosulfonyl)phenyl 362 SOCH₃ 5-pyrimidyl2-(methylaminosulfonyl)phenyl 363 SOCH₃ 5-pyrimidyl1-pyrrolidinocarbonyl 364 SOCH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 365SOCH₃ 5-pyrimidyl 4-morpholino 366 SOCH₃ 5-pyrimidyl2-(1′-CF₃-tetrazol-2-yl)phenyl 367 SOCH₃ 5-pyrimidyl4-morpholinocarbonyl 368 SOCH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 369SOCH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 370 SOCH₃ 5-pyrimidyl2-methylsulfonyl-1-imidazolyl 371 SOCH₃ 2-Cl-phenyl2-(aminosulfonyl)phenyl 372 SOCH₃ 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 373 SOCH₃ 2-Cl-phenyl1-pyrrolidinocarbonyl 374 SOCH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 375SOCH₃ 2-Cl-phenyl 4-morpholino 376 SOCH₃ 2-Cl-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 377 SOCH₃ 2-Cl-phenyl4-morpholinocarbonyl 378 SOCH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 379SOCH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 380 SOCH₃ 2-Cl-phenyl2-methylsulfonyl-1-imidazolyl 381 SOCH₃ 2-F-phenyl2-(aminosulfonyl)phenyl 382 SOCH₃ 2-F-phenyl2-(methylaminosulfonyl)phenyl 383 SOCH₃ 2-F-phenyl 1-pyrrolidinocarbonyl384 SOCH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 385 SOCH₃ 2-F-phenyl4-morpholino 386 SOCH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 387SOCH₃ 2-F-phenyl 4-morpholinocarbonyl 388 SOCH₃ 2-F-phenyl2-methyl-1-imidazolyl 389 SOCH₃ 2-F-phenyl 5-methyl-1-imidazolyl 390SOCH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 391 SOCH₃ 2,6-diF-phenyl2-(aminosulfonyl)phenyl 392 SOCH₃ 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 393 SOCH₃ 2,6-diF-phenyl1-pyrrolidinocarbonyl 394 SOCH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl395 SOCH₃ 2,6-diF-phenyl 4-morpholino 396 SOCH₃ 2,6-diF-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 397 SOCH₃ 2,6-diF-phenyl4-morpholinocarbonyl 398 SOCH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 399SOCH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 400 SOCH₃ 2,6-diF-phenyl2-methylsulfonyl-1-imidazolyl 401 SO₂CH₃ phenyl 2-(aminosulfonyl)phenyl402 SO₂CH₃ phenyl 2-(methylaminosulfonyl)phenyl 403 SO₂CH₃ phenyl1-pyrrolidinocarbonyl 404 SO₂CH₃ phenyl 2-(methylsulfonyl)phenyl 405SO₂CH₃ phenyl 4-morpholino 406 SO₂CH₃ phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 407 SO₂CH₃ phenyl 4-morpholinocarbonyl408 SO₂CH₃ phenyl 2-methyl-1-imidazolyl 409 SO₂CH₃ phenyl5-methyl-1-imidazolyl 410 SO₂CH₃ phenyl 2-methylsulfonyl-1-imidazolyl411 SO₂CH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 412 SO₂CH₃ 2-pyridyl2-(methylaminosulfonyl)phenyl 413 SO₂CH₃ 2-pyridyl 1-pyrrolidinocarbonyl414 SO₂CH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 415 SO₂CH₃ 2-pyridyl4-morpholino 416 SO₂CH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 417SO₂CH₃ 2-pyridyl 4-morpholinocarbonyl 418 SO₂CH₃ 2-pyridyl2-methyl-1-imidazolyl 419 SO₂CH₃ 2-pyridyl 5-methyl-1-imidazolyl 420SO₂CH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 421 SO₂CH₃ 3-pyridyl2-(aminosulfonyl)phenyl 422 SO₂CH₃ 3-pyridyl2-(methylaminosulfonyl)phenyl 423 SO₂CH₃ 3-pyridyl 1-pyrrolidinocarbonyl424 SO₂CH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 425 SO₂CH₃ 3-pyridyl4-morpholino 426 SO₂CH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 427SO₂CH₃ 3-pyridyl 4-morpholinocarbonyl 428 SO₂CH₃ 3-pyridyl2-methyl-1-imidazolyl 429 SO₂CH₃ 3-pyridyl 5-methyl-1-imidazolyl 430SO₂CH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 431 SO₂CH₃ 2-pyrimidyl2-(aminosulfonyl)phenyl 432 SO₂CH₃ 2-pyrimidyl2-(methylaminosulfonyl)phenyl 433 SO₂CH₃ 2-pyrimidyl1-pyrrolidinocarbonyl 434 SO₂CH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl435 SO₂CH₃ 2-pyrimidyl 4-morpholino 436 SO₂CH₃ 2-pyrimidyl2-(1′-CF₃-tetrazol-2-yl)phenyl 437 SO₂CH₃ 2-pyrimidyl4-morpholinocarbonyl 438 SO₂CH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 439SO₂CH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 440 SO₂CH₃ 2-pyrimidyl2-methylsulfonyl-1-imidazolyl 441 SO₂CH₃ 5-pyrimidyl2-(aminosulfonyl)phenyl 442 SO₂CH₃ 5-pyrimidyl2-(methylaminosulfonyl)phenyl 443 SO₂CH₃ 5-pyrimidyl1-pyrrolidinocarbonyl 444 SO₂CH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl445 SO₂CH₃ 5-pyrimidyl 4-morpholino 446 SO₂CH₃ 5-pyrimidyl2-(1′-CF₃-tetrazol-2-yl)phenyl 447 SO₂CH₃ 5-pyrimidyl4-morpholinocarbonyl 448 SO₂CH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 449SO₂CH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 450 SO₂CH₃ 5-pyrimidyl2-methylsulfonyl-1-imidazolyl 451 SO₂CH₃ 2-Cl-phenyl2-(aminosulfonyl)phenyl 452 SO₂CH₃ 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 453 SO₂CH₃ 2-Cl-phenyl1-pyrrolidinocarbonyl 454 SO₂CH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl455 SO₂CH₃ 2-Cl-phenyl 4-morpholino 456 SO₂CH₃ 2-Cl-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 457 SO₂CH₃ 2-Cl-phenyl4-morpholinocarbonyl 458 SO₂CH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 459SO₂CH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 460 SO₂CH₃ 2-Cl-phenyl2-methylsulfonyl-1-imidazolyl 461 SO₂CH₃ 2-F-phenyl2-(aminosulfonyl)phenyl 462 SO₂CH₃ 2-F-phenyl2-(methylaminosulfonyl)phenyl 463 SO₂CH₃ 2-F-phenyl1-pyrrolidinocarbonyl 464 SO₂CH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 465SO₂CH₃ 2-F-phenyl 4-morpholino 466 SO₂CH₃ 2-F-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 467 SO₂CH₃ 2-F-phenyl4-morpholinocarbonyl 468 SO₂CH₃ 2-F-phenyl 2-methyl-1-imidazolyl 469SO₂CH₃ 2-F-phenyl 5-methyl-1-imidazolyl 470 SO₂CH₃ 2-F-phenyl2-methylsulfonyl-1-imidazolyl 471 SO₂CH₃ 2,6-diF-phenyl2-(aminosulfonyl)phenyl 472 SO₂CH₃ 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 473 SO₂CH₃ 2,6-diF-phenyl1-pyrrolidinocarbonyl 474 SO₂CH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl475 SO₂CH₃ 2,6-diF-phenyl 4-morpholino 476 SO₂CH₃ 2,6-diF-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 477 SO₂CH₃ 2,6-diF-phenyl4-morpholinocarbonyl 478 SO₂CH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 479SO₂CH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 480 SO₂CH₃ 2,6-diF-phenyl2-methylsulfonyl-1-imidazolyl 481 CH₂NH—SO₂CH₃ phenyl2-(aminosulfonyl)phenyl 482 CH₂NH—SO₂CH₃ phenyl2-(methylaminosulfonyl)phenyl 483 CH₂NH—SO₂CH₃ phenyl1-pyrrolidinocarbonyl 484 CH₂NH—SO₂CH₃ phenyl 2-(methylsulfonyl)phenyl485 CH₂NH—SO₂CH₃ phenyl 4-morpholino 486 CH₂NH—SO₂CH₃ phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 487 CH₂NH—SO₂CH₃ phenyl4-morpholinocarbonyl 488 CH₂NH—SO₂CH₃ phenyl 2-methyl-1-imidazolyl 489CH₂NH—SO₂CH₃ phenyl 5-methyl-1-imidazolyl 490 CH₂NH—SO₂CH₃ phenyl2-methylsulfonyl-1-imidazolyl 491 CH₂NH—SO₂CH₃ 2-pyridyl2-(aminosulfonyl)phenyl 492 CH₂NH—SO₂CH₃ 2-pyridyl2-(methylaminosulfonyl)phenyl 493 CH₂NH—SO₂CH₃ 2-pyridyl1-pyrrolidinocarbonyl 494 CH₂NH—SO₂CH₃ 2-pyridyl2-(methylsulfonyl)phenyl 495 CH₂NH—SO₂CH₃ 2-pyridyl 4-morpholino 496CH₂NH—SO₂CH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 497 CH₂NH—SO₂CH₃2-pyridyl 4-morpholinocarbonyl 498 CH₂NH—SO₂CH₃ 2-pyridyl2-methyl-1-imidazolyl 499 CH₂NH—SO₂CH₃ 2-pyridyl 5-methyl-1-imidazolyl500 CH₂NH—SO₂CH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 501CH₂NH—SO₂CH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 502 CH₂NH—SO₂CH₃3-pyridyl 2-(methylaminosulfonyl)phenyl 503 CH₂NH—SO₂CH₃ 3-pyridyl1-pyrrolidinocarbonyl 504 CH₂NH—SO₂CH₃ 3-pyridyl2-(methylsulfonyl)phenyl 505 CH₂NH—SO₂CH₃ 3-pyridyl 4-morpholino 506CH₂NH—SO₂CH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 507 CH₂NH—SO₂CH₃3-pyridyl 4-morpholinocarbonyl 508 CH₂NH—SO₂CH₃ 3-pyridyl2-methyl-1-imidazolyl 509 CH₂NH—SO₂CH₃ 3-pyridyl 5-methyl-1-imidazolyl510 CH₂NH—SO₂CH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 511CH₂NH—SO₂CH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 512 CH₂NH—SO₂CH₃2-pyrimidyl 2-(methylaminosulfonyl)phenyl 513 CH₂NH—SO₂CH₃ 2-pyrimidyl1-pyrrolidinocarbonyl 514 CH₂NH—SO₂CH₃ 2-pyrimidyl2-(methylsulfonyl)phenyl 515 CH₂NH—SO₂CH₃ 2-pyrimidyl 4-morpholino 516CH₂NH—SO₂CH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 517 CH₂NH—SO₂CH₃2-pyrimidyl 4-morpholinocarbonyl 518 CH₂NH—SO₂CH₃ 2-pyrimidyl2-methyl-1-imidazolyl 519 CH₂NH—SO₂CH₃ 2-pyrimidyl 5-methyl-1-imidazolyl520 CH₂NH—SO₂CH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 521CH₂NH—SO₂CH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 522 CH₂NH—SO₂CH₃5-pyrimidyl 2-(methylaminosulfonyl)phenyl 523 CH₂NH—SO₂CH₃ 5-pyrimidyl1-pyrrolidinocarbonyl 524 CH₂NH—SO₂CH₃ 5-pyrimidyl2-(methylsulfonyl)phenyl 525 CH₂NH—SO₂CH₃ 5-pyrimidyl 4-morpholino 526CH₂NH—SO₂CH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 527 CH₂NH—SO₂CH₃5-pyrimidyl 4-morpholinocarbonyl 528 CH₂NH—SO₂CH₃ 5-pyrimidyl2-methyl-1-imidazolyl 529 CH₂NH—SO₂CH₃ 5-pyrimidyl 5-methyl-1-imidazolyl530 CH₂NH—SO₂CH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 531CH₂NH—SO₂CH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 532 CH₂NH—SO₂CH₃2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 533 CH₂NH—SO₂CH₃ 2-Cl-phenyl1-pyrrolidinocarbonyl 534 CH₂NH—SO₂CH₃ 2-Cl-phenyl2-(methylsulfonyl)phenyl 535 CH₂NH—SO₂CH₃ 2-Cl-phenyl 4-morpholino 536CH₂NH—SO₂CH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 537 CH₂NH—SO₂CH₃2-Cl-phenyl 4-morpholinocarbonyl 538 CH₂NH—SO₂CH₃ 2-Cl-phenyl2-methyl-1-imidazolyl 539 CH₂NH—SO₂CH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl540 CH₂NH—SO₂CH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 541CH₂NH—SO₂CH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 542 CH₂NH—SO₂CH₃2-F-phenyl 2-(methylaminosulfonyl)phenyl 543 CH₂NH—SO₂CH₃ 2-F-phenyl1-pyrrolidinocarbonyl 544 CH₂NH—SO₂CH₃ 2-F-phenyl2-(methylsulfonyl)phenyl 545 CH₂NH—SO₂CH₃ 2-F-phenyl 4-morpholino 546CH₂NH—SO₂CH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 547 CH₂NH—SO₂CH₃2-F-phenyl 4-morpholinocarbonyl 548 CH₂NH—SO₂CH₃ 2-F-phenyl2-methyl-1-imidazolyl 549 CH₂NH—SO₂CH₃ 2-F-phenyl 5-methyl-1-imidazolyl550 CH₂NH—SO₂CH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 551CH₂NH—SO₂CH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 552 CH₂NH—SO₂CH₃2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 553 CH₂NH—SO₂CH₃2,6-diF-phenyl 1-pyrrolidinocarbonyl 554 CH₂NH—SO₂CH₃ 2,6-diF-phenyl2-(methylsulfonyl)phenyl 555 CH₂NH—SO₂CH₃ 2,6-diF-phenyl 4-morpholino556 CH₂NH—SO₂CH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 557CH₂NH—SO₂CH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 558 CH₂NH—SO₂CH₃2,6-diF-phenyl 2-methyl-1-imidazolyl 559 CH₂NH—SO₂CH₃ 2,6-diF-phenyl5-methyl-1-imidazolyl 560 CH₂NH—SO₂CH₃ 2,6-diF-phenyl2-methylsulfonyl-1-imidazolyl 561 Cl phenyl 2-(aminosulfonyl)phenyl 562Cl phenyl 2-(methylaminosulfonyl)phenyl 563 Cl phenyl1-pyrrolidinocarbonyl 564 Cl phenyl 2-(methylsulfonyl)phenyl 565 Clphenyl 4-morpholino 566 Cl phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 567 Clphenyl 4-morpholinocarbonyl 568 Cl phenyl 2-methyl-1-imidazolyl 569 Clphenyl 5-methyl-1-imidazolyl 570 Cl phenyl 2-methylsulfonyl-1-imidazolyl571 Cl 2-pyridyl 2-(aminosulfonyl)phenyl 572 Cl 2-pyridyl2-(methylaminosulfonyl)phenyl 573 Cl 2-pyridyl 1-pyrrolidinocarbonyl 574Cl 2-pyridyl 2-(methylsulfonyl)phenyl 575 Cl 2-pyridyl 4-morpholino 576Cl 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 577 Cl 2-pyridyl4-morpholinocarbonyl 578 Cl 2-pyridyl 2-methyl-1-imidazolyl 579 Cl2-pyridyl 5-methyl-1-imidazolyl 580 Cl 2-pyridyl2-methylsulfonyl-1-imidazolyl 581 Cl 3-pyridyl 2-(aminosulfonyl)phenyl582 Cl 3-pyridyl 2-(methylaminosulfonyl)phenyl 583 Cl 3-pyridyl1-pyrrolidinocarbonyl 584 Cl 3-pyridyl 2-(methylsulfonyl)phenyl 585 Cl3-pyridyl 4-morpholino 586 Cl 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl587 Cl 3-pyridyl 4-morpholinocarbonyl 588 Cl 3-pyridyl2-methyl-1-imidazolyl 589 Cl 3-pyridyl 5-methyl-1-imidazolyl 590 Cl3-pyridyl 2-methylsulfonyl-1-imidazolyl 591 Cl 2-pyrimidyl2-(aminosulfonyl)phenyl 592 Cl 2-pyrimidyl 2-(methylaminosulfonyl)phenyl593 Cl 2-pyrimidyl 1-pyrrolidinocarbonyl 594 Cl 2-pyrimidyl2-(methylsulfonyl)phenyl 595 Cl 2-pyrimidyl 4-morpholino 596 Cl2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 597 Cl 2-pyrimidyl4-morpholinocarbonyl 598 Cl 2-pyrimidyl 2-methyl-1-imidazolyl 599 Cl2-pyrimidyl 5-methyl-1-imidazolyl 600 Cl 2-pyrimidyl2-methylsulfonyl-1-imidazolyl 601 Cl 5-pyrimidyl 2-(aminosulfonyl)phenyl602 Cl 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 603 Cl 5-pyrimidyl1-pyrrolidinocarbonyl 604 Cl 5-pyrimidyl 2-(methylsulfonyl)phenyl 605 Cl5-pyrimidyl 4-morpholino 606 Cl 5-pyrimidyl2-(1′-CF₃-tetrazol-2-yl)phenyl 607 Cl 5-pyrimidyl 4-morpholinocarbonyl608 Cl 5-pyrimidyl 2-methyl-1-imidazolyl 609 Cl 5-pyrimidyl5-methyl-1-imidazolyl 610 Cl 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl611 Cl 2-Cl-phenyl 2-(aminosulfonyl)phenyl 612 Cl 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 613 Cl 2-Cl-phenyl 1-pyrrolidinocarbonyl614 Cl 2-Cl-phenyl 2-(methylsulfonyl)phenyl 615 Cl 2-Cl-phenyl4-morpholino 616 Cl 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 617 Cl2-Cl-phenyl 4-morpholinocarbonyl 618 Cl 2-Cl-phenyl2-methyl-1-imidazolyl 619 Cl 2-Cl-phenyl 5-methyl-1-imidazolyl 620 Cl2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 621 Cl 2-F-phenyl2-(aminosulfonyl)phenyl 622 Cl 2-F-phenyl 2-(methylaminosulfonyl)phenyl623 Cl 2-F-phenyl 1-pyrrolidinocarbonyl 624 Cl 2-F-phenyl2-(methylsulfonyl)phenyl 625 Cl 2-F-phenyl 4-morpholino 626 Cl2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 627 Cl 2-F-phenyl4-morpholinocarbonyl 628 Cl 2-F-phenyl 2-methyl-1-imidazolyl 629 Cl2-F-phenyl 5-methyl-1-imidazolyl 630 Cl 2-F-phenyl2-methylsulfonyl-1-imidazolyl 631 Cl 2,6-diF-phenyl2-(aminosulfonyl)phenyl 632 Cl 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 633 Cl 2,6-diF-phenyl1-pyrrolidinocarbonyl 634 Cl 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 635Cl 2,6-diF-phenyl 4-morpholino 636 Cl 2,6-diF-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 637 Cl 2,6-diF-phenyl4-morpholinocarbonyl 638 Cl 2,6-diF-phenyl 2-methyl-1-imidazolyl 639 Cl2,6-diF-phenyl 5-methyl-1-imidazolyl 640 Cl 2,6-diF-phenyl2-methylsulfonyl-1-imidazolyl 641 F phenyl 2-(aminosulfonyl)phenyl 642 Fphenyl 2-(methylaminosulfonyl)phenyl 643 F phenyl 1-pyrrolidinocarbonyl644 F phenyl 2-(methylsulfonyl)phenyl 645 F phenyl 4-morpholino 646 Fphenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 647 F phenyl 4-morpholinocarbonyl648 F phenyl 2-methyl-1-imidazolyl 649 F phenyl 5-methyl-1-imidazolyl650 F phenyl 2-methylsulfonyl-1-imidazolyl 651 F 2-pyridyl2-(aminosulfonyl)phenyl 652 F 2-pyridyl 2-(methylaminosulfonyl)phenyl653 F 2-pyridyl 1-pyrrolidinocarbonyl 654 F 2-pyridyl2-(methylsulfonyl)phenyl 655 F 2-pyridyl 4-morpholino 656 F 2-pyridyl2-(1′-CF₃-tetrazol-2-yl)phenyl 657 F 2-pyridyl 4-morpholinocarbonyl 658F 2-pyridyl 2-methyl-1-imidazolyl 659 F 2-pyridyl 5-methyl-1-imidazolyl660 F 2-pyridyl 2-methylsulfonyl-1-imidazolyl 661 F 3-pyridyl2-(aminosulfonyl)phenyl 662 F 3-pyridyl 2-(methylaminosulfonyl)phenyl663 F 3-pyridyl 1-pyrrolidinocarbonyl 664 F 3-pyridyl2-(methylsulfonyl)phenyl 665 F 3-pyridyl 4-morpholino 666 F 3-pyridyl2-(1′-CF₃-tetrazol-2-yl)phenyl 667 F 3-pyridyl 4-morpholinocarbonyl 668F 3-pyridyl 2-methyl-1-imidazolyl 669 F 3-pyridyl 5-methyl-1-imidazolyl670 F 3-pyridyl 2-methylsulfonyl-1-imidazolyl 671 F 2-pyrimidyl2-(aminosulfonyl)phenyl 672 F 2-pyrimidyl 2-(methylaminosulfonyl)phenyl673 F 2-pyrimidyl 1-pyrrolidinocarbonyl 674 F 2-pyrimidyl2-(methylsulfonyl)phenyl 675 F 2-pyrimidyl 4-morpholino 676 F2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 677 F 2-pyrimidyl4-morpholinocarbonyl 678 F 2-pyrimidyl 2-methyl-1-imidazolyl 679 F2-pyrimidyl 5-methyl-1-imidazolyl 680 F 2-pyrimidyl2-methylsulfonyl-1-imidazolyl 681 F 5-pyrimidyl 2-(aminosulfonyl)phenyl682 F 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 683 F 5-pyrimidyl1-pyrrolidinocarbonyl 684 F 5-pyrimidyl 2-(methylsulfonyl)phenyl 685 F5-pyrimidyl 4-morpholino 686 F 5-pyrimidyl2-(1′-CF₃-tetrazol-2-yl)phenyl 687 F 5-pyrimidyl 4-morpholinocarbonyl688 F 5-pyrimidyl 2-methyl-1-imidazolyl 689 F 5-pyrimidyl5-methyl-1-imidazolyl 690 F 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl691 F 2-Cl-phenyl 2-(aminosulfonyl)phenyl 692 F 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 693 F 2-Cl-phenyl 1-pyrrolidinocarbonyl694 F 2-Cl-phenyl 2-(methylsulfonyl)phenyl 695 F 2-Cl-phenyl4-morpholino 696 F 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 697 F2-Cl-phenyl 4-morpholinocarbonyl 698 F 2-Cl-phenyl 2-methyl-1-imidazolyl699 F 2-Cl-phenyl 5-methyl-1-imidazolyl 700 F 2-Cl-phenyl2-methylsulfonyl-1-imidazolyl 701 F 2-F-phenyl 2-(aminosulfonyl)phenyl702 F 2-F-phenyl 2-(methylaminosulfonyl)phenyl 703 F 2-F-phenyl1-pyrrolidinocarbonyl 704 F 2-F-phenyl 2-(methylsulfonyl)phenyl 705 F2-F-phenyl 4-morpholino 706 F 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl707 F 2-F-phenyl 4-morpholinocarbonyl 708 F 2-F-phenyl2-methyl-1-imidazolyl 709 F 2-F-phenyl 5-methyl-1-imidazolyl 710 F2-F-phenyl 2-methylsulfonyl-1-imidazolyl 711 F 2,6-diF-phenyl2-(aminosulfonyl)phenyl 712 F 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 713 F 2,6-diF-phenyl 1-pyrrolidinocarbonyl714 F 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 715 F 2,6-diF-phenyl4-morpholino 716 F 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 717 F2,6-diF-phenyl 4-morpholinocarbonyl 718 F 2,6-diF-phenyl2-methyl-1-imidazolyl 719 F 2,6-diF-phenyl 5-methyl-1-imidazolyl 720 F2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 721 CO₂CH₃ phenyl2-(aminosulfonyl)phenyl 722 CO₂CH₃ phenyl 2-(methylaminosulfonyl)phenyl723 CO₂CH₃ phenyl 1-pyrrolidinocarbonyl 724 CO₂CH₃ phenyl2-(methylsulfonyl)phenyl 725 CO₂CH₃ phenyl 4-morpholino 726 CO₂CH₃phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 727 CO₂CH₃ phenyl4-morpholinocarbonyl 728 CO₂CH₃ phenyl 2-methyl-1-imidazolyl 729 CO₂CH₃phenyl 5-methyl-1-imidazolyl 730 CO₂CH₃ phenyl2-methylsulfonyl-1-imidazolyl 731 CO₂CH₃ 2-pyridyl2-(aminosulfonyl)phenyl 732 CO₂CH₃ 2-pyridyl2-(methylaminosulfonyl)phenyl 733 CO₂CH₃ 2-pyridyl 1-pyrrolidinocarbonyl734 CO₂CH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 735 CO₂CH₃ 2-pyridyl4-morpholino 736 CO₂CH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 737CO₂CH₃ 2-pyridyl 4-morpholinocarbonyl 738 CO₂CH₃ 2-pyridyl2-methyl-1-imidazolyl 739 CO₂CH₃ 2-pyridyl 5-methyl-1-imidazolyl 740CO₂CH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 741 CO₂CH₃ 3-pyridyl2-(aminosulfonyl)phenyl 742 CO₂CH₃ 3-pyridyl2-(methylaminosulfonyl)phenyl 743 CO₂CH₃ 3-pyridyl 1-pyrrolidinocarbonyl744 CO₂CH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 745 CO₂CH₃ 3-pyridyl4-morpholino 746 CO₂CH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 747CO₂CH₃ 3-pyridyl 4-morpholinocarbonyl 748 CO₂CH₃ 3-pyridyl2-methyl-1-imidazolyl 749 CO₂CH₃ 3-pyridyl 5-methyl-1-imidazolyl 750CO₂CH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 751 CO₂CH₃ 2-pyrimidyl2-(aminosulfonyl)phenyl 752 CO₂CH₃ 2-pyrimidyl2-(methylaminosulfonyl)phenyl 753 CO₂CH₃ 2-pyrimidyl1-pyrrolidinocarbonyl 754 CO₂CH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl755 CO₂CH₃ 2-pyrimidyl 4-morpholino 756 CO₂CH₃ 2-pyrimidyl2-(1′-CF₃-tetrazol-2-yl)phenyl 757 CO₂CH₃ 2-pyrimidyl4-morpholinocarbonyl 758 CO₂CH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 759CO₂CH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 760 CO₂CH₃ 2-pyrimidyl2-methylsulfonyl-1-imidazolyl 761 CO₂CH₃ 5-pyrimidyl2-(aminosulfonyl)phenyl 762 CO₂CH₃ 5-pyrimidyl2-(methylaminosulfonyl)phenyl 763 CO₂CH₃ 5-pyrimidyl1-pyrrolidinocarbonyl 764 CO₂CH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl765 CO₂CH₃ 5-pyrimidyl 4-morpholino 766 CO₂CH₃ 5-pyrimidyl2-(1′-CF₃-tetrazol-2-yl)phenyl 767 CO₂CH₃ 5-pyrimidyl4-morpholinocarbonyl 768 CO₂CH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 769CO₂CH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 770 CO₂CH₃ 5-pyrimidyl2-methylsulfonyl-1-imidazolyl 771 CO₂CH₃ 2-Cl-phenyl2-(aminosulfonyl)phenyl 772 CO₂CH₃ 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 773 CO₂CH₃ 2-Cl-phenyl1-pyrrolidinocarbonyl 774 CO₂CH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl775 CO₂CH₃ 2-Cl-phenyl 4-morpholino 776 CO₂CH₃ 2-Cl-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 777 CO₂CH₃ 2-Cl-phenyl4-morpholinocarbonyl 778 CO₂CH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 779CO₂CH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 780 CO₂CH₃ 2-Cl-phenyl2-methylsulfonyl-1-imidazolyl 781 CO₂CH₃ 2-F-phenyl2-(aminosulfonyl)phenyl 782 CO₂CH₃ 2-F-phenyl2-(methylaminosulfonyl)phenyl 783 CO₂CH₃ 2-F-phenyl1-pyrrolidinocarbonyl 784 CO₂CH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 785CO₂CH₃ 2-F-phenyl 4-morpholino 786 CO₂CH₃ 2-F-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 787 CO₂CH₃ 2-F-phenyl4-morpholinocarbonyl 788 CO₂CH₃ 2-F-phenyl 2-methyl-1-imidazolyl 789CO₂CH₃ 2-F-phenyl 5-methyl-1-imidazolyl 790 CO₂CH₃ 2-F-phenyl2-methylsulfonyl-1-imidazolyl 791 CO₂CH₃ 2,6-diF-phenyl2-(aminosulfonyl)phenyl 792 CO₂CH₃ 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 793 CO₂CH₃ 2,6-diF-phenyl1-pyrrolidinocarbonyl 794 CO₂CH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl795 CO₂CH₃ 2,6-diF-phenyl 4-morpholino 796 CO₂CH₃ 2,6-diF-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 797 CO₂CH₃ 2,6-diF-phenyl4-morpholinocarbonyl 798 CO₂CH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 799CO₂CH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 800 CO₂CH₃ 2,6-diF-phenyl2-methylsulfonyl-1-imidazolyl 801 CH₂OCH₃ phenyl 2-(aminosulfonyl)phenyl802 CH₂OCH₃ phenyl 2-(methylaminosulfonyl)phenyl 803 CH₂OCH₃ phenyl1-pyrrolidinocarbonyl 804 CH₂OCH₃ phenyl 2-(methylsulfonyl)phenyl 805CH₂OCH₃ phenyl 4-morpholino 806 CH₂OCH₃ phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 807 CH₂OCH₃ phenyl 4-morpholinocarbonyl808 CH₂OCH₃ phenyl 2-methyl-1-imidazolyl 809 CH₂OCH₃ phenyl5-methyl-1-imidazolyl 810 CH₂OCH₃ phenyl 2-methylsulfonyl-1-imidazolyl811 CH₂OCH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 812 CH₂OCH₃ 2-pyridyl2-(methylaminosulfonyl)phenyl 813 CH₂OCH₃ 2-pyridyl1-pyrrolidinocarbonyl 814 CH₂OCH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 815CH₂OCH₃ 2-pyridyl 4-morpholino 816 CH₂OCH₃ 2-pyridyl2-(1′-CF₃-tetrazol-2-yl)phenyl 817 CH₂OCH₃ 2-pyridyl4-morpholinocarbonyl 818 CH₂OCH₃ 2-pyridyl 2-methyl-1-imidazolyl 819CH₂OCH₃ 2-pyridyl 5-methyl-1-imidazolyl 820 CH₂OCH₃ 2-pyridyl2-methylsulfonyl-1-imidazolyl 821 CH₂OCH₃ 3-pyridyl2-(aminosulfonyl)phenyl 822 CH₂OCH₃ 3-pyridyl2-(methylaminosulfonyl)phenyl 823 CH₂OCH₃ 3-pyridyl1-pyrrolidinocarbonyl 824 CH₂OCH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 825CH₂OCH₃ 3-pyridyl 4-morpholino 826 CH₂OCH₃ 3-pyridyl2-(1′-CF₃-tetrazol-2-yl)phenyl 827 CH₂OCH₃ 3-pyridyl4-morpholinocarbonyl 828 CH₂OCH₃ 3-pyridyl 2-methyl-1-imidazolyl 829CH₂OCH₃ 3-pyridyl 5-methyl-1-imidazolyl 830 CH₂OCH₃ 3-pyridyl2-methylsulfonyl-1-imidazolyl 831 CH₂OCH₃ 2-pyrimidyl2-(aminosulfonyl)phenyl 832 CH₂OCH₃ 2-pyrimidyl2-(methylaminosulfonyl)phenyl 833 CH₂OCH₃ 2-pyrimidyl1-pyrrolidinocarbonyl 834 CH₂OCH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl835 CH₂OCH₃ 2-pyrimidyl 4-morpholino 836 CH₂OCH₃ 2-pyrimidyl2-(1′-CF₃-tetrazol-2-yl)phenyl 837 CH₂OCH₃ 2-pyrimidyl4-morpholinocarbonyl 838 CH₂OCH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 839CH₂OCH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 840 CH₂OCH₃ 2-pyrimidyl2-methylsulfonyl-1-imidazolyl 841 CH₂OCH₃ 5-pyrimidyl2-(aminosulfonyl)phenyl 842 CH₂OCH₃ 5-pyrimidyl2-(methylaminosulfonyl)phenyl 843 CH₂OCH₃ 5-pyrimidyl1-pyrrolidinocarbonyl 844 CH₂OCH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl845 CH₂OCH₃ 5-pyrimidyl 4-morpholino 846 CH₂OCH₃ 5-pyrimidyl2-(1′-CF₃-tetrazol-2-yl)phenyl 847 CH₂OCH₃ 5-pyrimidyl4-morpholinocarbonyl 848 CH₂OCH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 849CH₂OCH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 850 CH₂OCH₃ 5-pyrimidyl2-methylsulfonyl-1-imidazolyl 851 CH₂OCH₃ 2-Cl-phenyl2-(aminosulfonyl)phenyl 852 CH₂OCH₃ 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 853 CH₂OCH₃ 2-Cl-phenyl1-pyrrolidinocarbonyl 854 CH₂OCH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl855 CH₂OCH₃ 2-Cl-phenyl 4-morpholino 856 CH₂OCH₃ 2-Cl-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 857 CH₂OCH₃ 2-Cl-phenyl4-morpholinocarbonyl 858 CH₂OCH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 859CH₂OCH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 860 CH₂OCH₃ 2-Cl-phenyl2-methylsulfonyl-1-imidazolyl 861 CH₂OCH₃ 2-F-phenyl2-(aminosulfonyl)phenyl 862 CH₂OCH₃ 2-F-phenyl2-(methylaminosulfonyl)phenyl 863 CH₂OCH₃ 2-F-phenyl1-pyrrolidinocarbonyl 864 CH₂OCH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl865 CH₂OCH₃ 2-F-phenyl 4-morpholino 866 CH₂OCH₃ 2-F-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 867 CH₂OCH₃ 2-F-phenyl4-morpholinocarbonyl 868 CH₂OCH₃ 2-F-phenyl 2-methyl-1-imidazolyl 869CH₂OCH₃ 2-F-phenyl 5-methyl-1-imidazolyl 870 CH₂OCH₃ 2-F-phenyl2-methylsulfonyl-1-imidazolyl 871 CH₂OCH₃ 2,6-diF-phenyl2-(aminosulfonyl)phenyl 872 CH₂OCH₃ 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 873 CH₂OCH₃ 2,6-diF-phenyl1-pyrrolidinocarbonyl 874 CH₂OCH₃ 2,6-diF-phenyl2-(methylsulfonyl)phenyl 875 CH₂OCH₃ 2,6-diF-phenyl 4-morpholino 876CH₂OCH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 877 CH₂OCH₃2,6-diF-phenyl 4-morpholinocarbonyl 878 CH₂OCH₃ 2,6-diF-phenyl2-methyl-1-imidazolyl 879 CH₂OCH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl880 CH₂OCH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 881 CONH₂phenyl 2-(aminosulfonyl)phenyl 882 CONH₂ phenyl2-(methylaminosulfonyl)phenyl 883 CONH₂ phenyl 1-pyrrolidinocarbonyl 884CONH₂ phenyl 2-(methylsulfonyl)phenyl 885 CONH₂ phenyl 4-morpholino 886CONH₂ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 887 CONH₂ phenyl4-morpholinocarbonyl 888 CONH₂ phenyl 2-methyl-1-imidazolyl 889 CONH₂phenyl 5-methyl-1-imidazolyl 890 CONH₂ phenyl2-methylsulfonyl-1-imidazolyl 891 CONH₂ 2-pyridyl2-(aminosulfonyl)phenyl 892 CONH₂ 2-pyridyl2-(methylaminosulfonyl)phenyl 893 CONH₂ 2-pyridyl 1-pyrrolidinocarbonyl894 CONH₂ 2-pyridyl 2-(methylsulfonyl)phenyl 895 CONH₂ 2-pyridyl4-morpholino 896 CONH₂ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 897CONH₂ 2-pyridyl 4-morpholinocarbonyl 898 CONH₂ 2-pyridyl2-methyl-1-imidazolyl 899 CONH₂ 2-pyridyl 5-methyl-1-imidazolyl 900CONH₂ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 901 CONH₂ 3-pyridyl2-(aminosulfonyl)phenyl 902 CONH₂ 3-pyridyl2-(methylaminosulfonyl)phenyl 903 CONH₂ 3-pyridyl 1-pyrrolidinocarbonyl904 CONH₂ 3-pyridyl 2-(methylsulfonyl)phenyl 905 CONH₂ 3-pyridyl4-morpholino 906 CONH₂ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 907CONH₂ 3-pyridyl 4-morpholinocarbonyl 908 CONH₂ 3-pyridyl2-methyl-1-imidazolyl 909 CONH₂ 3-pyridyl 5-methyl-1-imidazolyl 910CONH₂ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 911 CONH₂ 2-pyrimidyl2-(aminosulfonyl)phenyl 912 CONH₂ 2-pyrimidyl2-(methylaminosulfonyl)phenyl 913 CONH₂ 2-pyrimidyl1-pyrrolidinocarbonyl 914 CONH₂ 2-pyrimidyl 2-(methylsulfonyl)phenyl 915CONH₂ 2-pyrimidyl 4-morpholino 916 CONH₂ 2-pyrimidyl2-(1′-CF₃-tetrazol-2-yl)phenyl 917 CONH₂ 2-pyrimidyl4-morpholinocarbonyl 918 CONH₂ 2-pyrimidyl 2-methyl-1-imidazolyl 919CONH₂ 2-pyrimidyl 5-methyl-1-imidazolyl 920 CONH₂ 2-pyrimidyl2-methylsulfonyl-1-imidazolyl 921 CONH₂ 5-pyrimidyl2-(aminosulfonyl)phenyl 922 CONH₂ 5-pyrimidyl2-(methylaminosulfonyl)phenyl 923 CONH₂ 5-pyrimidyl1-pyrrolidinocarbonyl 924 CONH₂ 5-pyrimidyl 2-(methylsulfonyl)phenyl 925CONH₂ 5-pyrimidyl 4-morpholino 926 CONH₂ 5-pyrimidyl2-(1′-CF₃-tetrazol-2-yl)phenyl 927 CONH₂ 5-pyrimidyl4-morpholinocarbonyl 928 CONH₂ 5-pyrimidyl 2-methyl-1-imidazolyl 929CONH₂ 5-pyrimidyl 5-methyl-1-imidazolyl 930 CONH₂ 5-pyrimidyl2-methylsulfonyl-1-imidazolyl 931 CONH₂ 2-Cl-phenyl2-(aminosulfonyl)phenyl 932 CONH₂ 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 933 CONH₂ 2-Cl-phenyl1-pyrrolidinocarbonyl 934 CONH₂ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 935CONH₂ 2-Cl-phenyl 4-morpholino 936 CONH₂ 2-Cl-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 937 CONH₂ 2-Cl-phenyl4-morpholinocarbonyl 938 CONH₂ 2-Cl-phenyl 2-methyl-1-imidazolyl 939CONH₂ 2-Cl-phenyl 5-methyl-1-imidazolyl 940 CONH₂ 2-Cl-phenyl2-methylsulfonyl-1-imidazolyl 941 CONH₂ 2-F-phenyl2-(aminosulfonyl)phenyl 942 CONH₂ 2-F-phenyl2-(methylaminosulfonyl)phenyl 943 CONH₂ 2-F-phenyl 1-pyrrolidinocarbonyl944 CONH₂ 2-F-phenyl 2-(methylsulfonyl)phenyl 945 CONH₂ 2-F-phenyl4-morpholino 946 CONH₂ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 947CONH₂ 2-F-phenyl 4-morpholinocarbonyl 948 CONH₂ 2-F-phenyl2-methyl-1-imidazolyl 949 CONH₂ 2-F-phenyl 5-methyl-1-imidazolyl 950CONH₂ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 951 CONH₂ 2,6-diF-phenyl2-(aminosulfonyl)phenyl 952 CONH₂ 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 953 CONH₂ 2,6-diF-phenyl1-pyrrolidinocarbonyl 954 CONH₂ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl955 CONH₂ 2,6-diF-phenyl 4-morpholino 956 CONH₂ 2,6-diF-phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 957 CONH₂ 2,6-diF-phenyl4-morpholinocarbonyl 958 CONH₂ 2,6-diF-phenyl 2-methyl-1-imidazolyl 959CONH₂ 2,6-diF-phenyl 5-methyl-1-imidazolyl 960 CONH₂ 2,6-diF-phenyl2-methylsulfonyl-1-imidazolyl

TABLE 2

a

b

c

d

e

f

g

h

i

j

k

l

m

n

o

p

q

r

s

t

u

v

w

x

y

z

aa

bb

cc

dd

ee

ff

gg

hh

ii

jj

kk

ll

mm

nn

oo

pp

qq

rr

ss Ex # A B  1 phenyl 2-(aminosulfonyl)phenyl  2 phenyl2-(methylaminosulfonyl)phenyl  3 phenyl 1-pyrrolidinocarbonyl  4 phenyl2-(methylsulfonyl)phenyl  5 phenyl 4-morpholino  6 phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl  7 phenyl 4-morpholinocarbonyl  8 phenyl2-methyl-1-imidazolyl  9 phenyl 5-methyl-1-imidazolyl 10 phenyl2-methylsulfonyl-1-imidazolyl 11 2-pyridyl 2-(aminosulfonyl)phenyl 122-pyridyl 2-(methylaminosulfonyl)phenyl 13 2-pyridyl1-pyrrolidinocarbonyl 14 2-pyridyl 2-(methylsulfonyl)phenyl 15 2-pyridyl4-morpholino 16 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 17 2-pyridyl4-morpholinocarbonyl 18 2-pyridyl 2-methyl-1-imidazolyl 19 2-pyridyl5-methyl-1-imidazolyl 20 2-pyridyl 2-methylsulfonyl-1-imidazolyl 213-pyridyl 2-(aminosulfonyl)phenyl 22 3-pyridyl2-(methylaminosulfonyl)phenyl 23 3-pyridyl 1-pyrrolidinocarbonyl 243-pyridyl 2-(methylsulfonyl)phenyl 25 3-pyridyl 4-morpholino 263-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 27 3-pyridyl4-morpholinocarbonyl 28 3-pyridyl 2-methyl-1-imidazolyl 29 3-pyridyl5-methyl-1-imidazolyl 30 3-pyridyl 2-methylsulfonyl-1-imidazolyl 312-pyrimidyl 2-(aminosulfonyl)phenyl 32 2-pyrimidyl2-(methylaminosulfonyl)phenyl 33 2-pyrimidyl 1-pyrrolidinocarbonyl 342-pyrimidyl 2-(methylsulfonyl)phenyl 35 2-pyrimidyl 4-morpholino 362-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 37 2-pyrimidyl4-morpholinocarbonyl 38 2-pyrimidyl 2-methyl-1-imidazolyl 39 2-pyrimidyl5-methyl-1-imidazolyl 40 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 415-pyrimidyl 2-(aminosulfonyl)phenyl 42 5-pyrimidyl2-(methylaminosulfonyl)phenyl 43 5-pyrimidyl 1-pyrrolidinocarbonyl 445-pyrimidyl 2-(methylsulfonyl)phenyl 45 5-pyrimidyl 4-morpholino 465-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 47 5-pyrimidyl4-morpholinocarbonyl 48 5-pyrimidyl 2-methyl-1-imidazolyl 49 5-pyrimidyl5-methyl-1-imidazolyl 50 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 512-Cl-phenyl 2-(aminosulfonyl)phenyl 52 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 53 2-Cl-phenyl 1-pyrrolidinocarbonyl 542-Cl-phenyl 2-(methylsulfonyl)phenyl 55 2-Cl-phenyl 4-morpholino 562-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 57 2-Cl-phenyl4-morpholinocarbonyl 58 2-Cl-phenyl 2-methyl-1-imidazolyl 59 2-Cl-phenyl5-methyl-1-imidazolyl 60 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 612-F-phenyl 2-(aminosulfonyl)phenyl 62 2-F-phenyl2-(methylaminosulfonyl)phenyl 63 2-F-phenyl 1-pyrrolidinocarbonyl 642-F-phenyl 2-(methylsulfonyl)phenyl 65 2-F-phenyl 4-morpholino 662-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 67 2-F-phenyl4-morpholinocarbonyl 68 2-F-phenyl 2-methyl-1-imidazolyl 69 2-F-phenyl5-methyl-1-imidazolyl 70 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 712,6-diF-phenyl 2-(aminosulfonyl)phenyl 72 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 73 2,6-diF-phenyl 1-pyrrolidinocarbonyl 742,6-diF-phenyl 2-(methylsulfonyl)phenyl 75 2,6-diF-phenyl 4-morpholino76 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 77 2,6-diF-phenyl4-morpholinocarbonyl 78 2,6-diF-phenyl 2-methyl-1-imidazolyl 792,6-diF-phenyl 5-methyl-1-imidazolyl 80 2,6-diF-phenyl2-methylsulfonyl-1-imidazolyl

UTILITY

The compounds of this invention are useful as anticoagulants for thetreatment or prevention of thromboembolic disorders in mammals. The term“thromboembolic disorders” as used herein includes arterial or venouscardiovascular or cerebrovascular thromboembolic disorders, including,for example, unstable angina, first or recurrent myocardial infarction,ischemic sudden death, transient ischemic attack, stroke,atherosclerosis, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary and cerebral arterialthrombosis, cerebral embolism, kidney embolisms, and pulmonaryembolisms. The anticoagulant effect of compounds of the presentinvention is believed to be due to inhibition of factor Xa or thrombin.

The effectiveness of compounds of the present invention as inhibitors offactor Xa was determined using purified human factor Xa and syntheticsubstrate. The rate of factor Xa hydrolysis of chromogenic substrateS2222 (Kabi Pharmacia, Franklin, Ohio) was measured both in the absenceand presence of compounds of the present invention. Hydrolysis of thesubstrate resulted in the release of pNA, which was monitoredspectrophotometrically by measuring the increase in absorbance at 405nM. A decrease in the rate of absorbance change at 405 nm in thepresence of inhibitor is indicative of enzyme inhibition. The results ofthis assay are expressed as inhibitory constant, K_(i).

Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant,K_(m), for substrate hydrolysis was determined at 25° C. using themethod of Lineweaver and Burk. Values of K_(i) were determined byallowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, SouthBend, Ind.) to react with the substrate (0.20 mM-1 mM) in the presenceof inhibitor. Reactions were allowed to go for 30 minutes and thevelocities (rate of absorbance change vs time) were measured in the timeframe of 25-30 minutes. The following relationship was used to calculateK_(i) values:

 (v _(o) 31 v _(s))/v _(s) =I/(K _(i)(1+S/K _(m)))

where:

v_(o) is the velocity of the control in the absence of inhibitor;

v_(s) is the velocity in the presence of inhibitor;

I is the concentration of inhibitor;

K_(i) is the dissociation constant of the enzyme:inhibitor complex;

S is the concentration of substrate;

K_(m) is the Michaelis constant.

Using the methodology described above, a compound of the presentinvention were found to exhibit a K_(i) of ≦10 μM, thereby confirmingthe utility of the compounds of the present invention as effective Xainhibitors.

The antithrombotic effect of compounds of the present invention can bedemonstrated in a rabbit arteric-venous (AV) shunt thrombosis model. Inthis model, rabbits weighing 2-3 kg anesthetized with a mixture ofxylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. Asaline-filled AV shunt device is connected between the femoral arterialand the femoral venous cannulae. The AV shunt device consists of a pieceof 6-cm tygon tubing which contains a piece of silk thread. Blood willflow from the femoral artery via the AV-shunt into the femoral vein. Theexposure of flowing blood to a silk thread will induce the formation ofa significant thrombus. After forty minutes, the shunt is disconnectedand the silk thread covered with thrombus is weighed. Test agents orvehicle will be given (i.v., i.p., s.c., or orally) prior to the openingof the AV shunt. The percentage inhibition of thrombus formation isdetermined for each treatment group. The ID50 values (dose whichproduces 50% inhibition of thrombus formation) are estimated by linearregression.

The compounds of formula (I) may also be useful as inhibitors of serineproteases, notably human thrombin, plasma kallikrein and plasmin.Because of their inhibitory action, these compounds are indicated foruse in the prevention or treatment of physiological reactions, bloodcoagulation and inflammation, catalyzed by the aforesaid class ofenzymes. Specifically, the compounds have utility as drugs for thetreatment of diseases arising from elevated thrombin activity such asmyocardial infarction, and as reagents used as anticoagulants in theprocessing of blood to plasma for diagnostic and other commercialpurposes.

Some compounds of the present invention were shown to be direct actinginhibitors of the serine protease thrombin by their ability to inhibitthe cleavage of small molecule substrates by thrombin in a purifiedsystem. In vitro inhibition constants were determined by the methoddescribed by Kettner et al. in J. Biol. Chem. 265, 18289-18297 (1990),herein incorporated by reference. In these assays, thrombin-mediatedhydrolysis of the chromogenic substrate S2238 (Helena Laboratories,Beaumont, Tex.) was monitored spectrophotometrically. Addition of aninhibitor to the assay mixture results in decreased absorbance and isindicative of thrombin inhibition. Human thrombin (Enzyme ResearchLaboratories, Inc., South Bend, Ind.) at a concentration of 0.2 nM in0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000,was incubated with various substrate concentrations ranging from 0.20 to0.02 mM. After 25 to 30 minutes of incubation, thrombin activity wasassayed by monitoring the rate of increase in absorbance at 405 nm whicharises owing to substrate hydrolysis. Inhibition constants were derivedfrom reciprocal plots of the reaction velocity as a function ofsubstrate concentration using the standard method of Lineweaver andBurk. Using the methodology described above, some compounds of thisinvention were evaluated and found to exhibit a K_(i) of less than 10μm, thereby confirming the utility of the compounds of the presentinvention as effective thrombin inhibitors.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. Theseinclude other anti-coagulant or coagulation inhibitory agents,anti-platelet or platelet inhibitory agents, thrombin inhibitors, orthrombolytic or fibrinolytic agents.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of Formula I that, when administered alone or incombination with an additional therapeutic agent to a mammal, iseffective to prevent or ameliorate the thromboembolic disease conditionor the progression of the disease.

By “administered in combination” or “combination therapy” it is meantthat the compound of Formula I and one or more additional therapeuticagents are administered concurrently to the mammal being treated. Whenadministered in combination each component may be administered at thesame time or sequentially in any order at different points in time.Thus, each component may be administered separately but sufficientlyclosely in time so as to provide the desired therapeutic effect. Otheranticoagulant agents (or coagulation inhibitory agents) that may be usedin combination with the compounds of this invention include warfarin andheparin, as well as other factor Xa inhibitors such as those describedin the publications identified above under Background of the Invention.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function such as byinhibiting the aggregation, adhesion or granular secretion of platelets.Such agents include, but are not limited to, the various knownnon-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam,diclofenac, sulfinpyrazone, and piroxicam, including pharmaceuticallyacceptable salts or prodrugs thereof. Of the NSAIDS, aspirin(acetylsalicyclic acid or ASA), and piroxicam are preferred. Othersuitable anti-platelet agents include ticlopidine, includingpharmaceutically acceptable salts or prodrugs thereof. Ticlopidine isalso a preferred compound since it is known to be gentle on thegastro-intestinal tract in use. Still other suitable platelet inhibitoryagents include IIb/IIIa antagonists, thromboxane-A2-receptor antagonistsand thromboxane-A2-synthetase inhibitors, as well as pharmaceuticallyacceptable salts or prodrugs thereof.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the granular secretion of plasminogen activator inhibitor-1and/or serotonin) and/or fibrin formation are disrupted. A number ofthrombin inhibitors are known to one of skill in the art and theseinhibitors are contemplated to be used in combination with the presentcompounds. Such inhibitors include, but are not limited to, boroargininederivatives, boropeptides, heparins, hirudin and argatroban, includingpharmaceutically acceptable salts and prodrugs thereof. Boroargininederivatives and boropeptides include N-acetyl and peptide derivatives ofboronic acid, such as C-terminal a-aminoboronic acid derivatives oflysine, ornithine, arginine, homoarginine and correspondingisothiouronium analogs thereof. The term hirudin, as used herein,includes suitable derivatives or analogs of hirudin, referred to hereinas hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitorsinclude compounds described in Kettner et al., U.S. Pat. No. 5,187,157and European Patent Application Publication Number 293 881 A2, thedisclosures of which are hereby incorporated herein by reference. Othersuitable boroarginine derivatives and boropeptide thrombin inhibitorsinclude those disclosed in PCT Application Publication Number 92/07869and European Patent Application Publication Number 471,651 A2, thedisclosures of which are hereby incorporated herein by reference.

The term thrombolytics (or fibrinolytic) agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator,anistreplase, urokinase or streptokinase, including pharmaceuticallyacceptable salts or prodrugs thereof. The term anistreplase, as usedherein, refers to anisoylated plasminogen streptokinase activatorcomplex, as described, for example, in European Patent Application No.028,489, the disclosure of which is hereby incorporated herein byreference herein. The term urokinase, as used herein, is intended todenote both dual and single chain urokinase, the latter also beingreferred to herein as prourokinase.

Administration of the compounds of Formula I of the invention incombination with such additional therapeutic agent, may afford anefficacy advantage over the compounds and agents alone, and may do sowhile permitting the use of lower doses of each. A lower dosageminimizes the potential of side effects, thereby providing an increasedmargin of safety.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of factor Xa. Such compoundsmay be provided in a commercial kit, for example, for use inpharmaceutical research involving factor Xa. For example, a compound ofthe present invention could be used as a reference in an assay tocompare its known activity to a compound with an unknown activity. Thiswould ensure the experimenter that the assay was being performedproperly and provide a basis for comparison, especially if the testcompound was a derivative of the reference compound. When developing newassays or protocols, compounds according to the present invention couldbe used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving factor Xa. For example, the presence of factor Xa in anunknown sample could be determined by addition of chromogenic substrateS2222 to a series of solutions containing test sample and optionally oneof the compounds of the present invention. If production of pNA isobserved in the solutions containing test sample, but not in thepresence of a compound of the present invention, then one would concludefactor Xa was present.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient,and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Reminaton'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of the compound of Formula I and about 1 to 7.5milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 10 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 5milligrams per dosage unit.

Where the compounds of Formula I are administered in combination with ananti-platelet agent, by way of general guidance, typically a dailydosage may be about 0.01 to 25 milligrams of the compound of Formula Iand about 50 to 150 milligrams of the anti-platelet agent, preferablyabout 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3milligrams of antiplatelet agents, per kilogram of patient body weight.

Where the compounds of Formula I are adminstered in combination withthrombolytic agent, typically a daily dosage may be about 0.1 to 1milligrams of the compound of Formula I, per kilogram of patient bodyweight and, in the case of the thrombolytic agents, the usual dosage ofthe thrombolyic agent when administered alone may be reduced by about70-80% when administered with a compound of Formula I.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of Formula I and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise that as specifically describedherein.

What is claimed is:
 1. A compound of formula I:

or a steroisomer or pharmaceutically acceptable salt thereof, wherein;M¹ is CR^(1c); M² is CR^(1a)R^(1a); D is selected from C(═NR⁸)NR⁷R⁹,NHC(═NR⁸)NR⁷R⁹, NR⁸CH(═NR⁷), C(O)NR⁷R⁸, and CR⁸R⁹NR⁷R⁸; E is selectedfrom phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, and piperidinylsubstituted with 1 R; alternatively, D—E—G together represent pyridylsubstituted with 1 R; R is selected from H, Cl, F, Br, I, (CH₂)_(t)OR³,C₁₋₄ alkyl, OCF₃, CF₃, C(O)NR⁷R⁸, and (CR⁸R⁹)_(t)NR⁷R⁸; G is selectedfrom NHCH₂, OCH₂, and SCH₂, provided that when s is 0, then G is absent;Z is selected from a C₁₋₄ alkylene, (CH₂)_(r)O(CH₂)_(r),(CH₂)_(r)NR³(CH₂)_(r), (CH₂)_(r)C(O)(CH₂)_(r), (CH₂)_(r)C(O)O(CH₂)_(r),(CH₂)_(r)OC(O)(CH₂)_(r), (CH₂)_(r)C(O)NR³(CH₂)_(r),(CH₂)_(r)NR³C(O)(CH₂)_(r), (CH₂)_(r)OC(O)O(CH₂)_(r),(CH₂)_(r)OC(O)NR³(CH₂)_(r), (CH₂)_(r)NR³C(O)O(CH₂)_(r),(CH₂)_(r)NR³C(O)NR³(CH₂)_(r), (CH₂)_(r)S(O)_(p)(CH₂)_(r),(CH₂)_(r)SO₂NR³(CH₂)_(r), (CH₂)_(r)NR³SO₂(CH₂)_(r), and(CH₂)_(r)NR³SO₂NR³(CH₂)_(r), provided that Z does not form a N—N, N—O,N—S, NCH₂N, NCH₂O, or NCH₂S bond with group A; R^(1a) and R^(1b) are, ateach occurrence, independently selected from H, —(CH₂)_(r)—R^(1′),NCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″), N(CH₂)₂(CH₂)_(t)R^(1′),O(CH₂)₂(CH₂)_(t)R^(1′), and S(CH₂)₂(CH₂)_(t)R^(1′); R^(1c) is selectedfrom H, —(CH₂)_(q)—R^(1′), C₁₋₃ alkyl, C(O)R^(2c), (CF₂)_(r)CO₂R^(2c),C(O)NR²R^(2a), C₃₋₆ carbocyclic residue substituted 0-2 R⁴, and 5-10membered heterocyclic system comprising carbon atoms and from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted 0-2 R⁴; R^(1′) is selected from H, C₁₋₃ alkyl, halo,(CF₂)_(r)CF₃, OR², NR²R^(2a), C(O)R^(2c), OC(O)R², (CF₂)_(r)CO₂R^(2c),S(O)_(p)R^(2b), NR²(CH₂)_(r)OR², NR²C(O)R^(2b), NR²C(O)NHR^(2b),NR²C(O)₂R^(2a), OC(O)NR^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂R^(2b),C₃₋₆ carbocyclic residue substituted 0-2 R⁴, and 5-10 memberedheterocyclic system comprising carbon atoms and from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted 0-2 R⁴;R^(1″) is selected from H, C(O)R^(2b), C(O)NR²R^(2a), S(O)R^(2b),S(O)₂R^(2b), and SO₂NR²R^(2a); R², at each occurrence, is selected fromH, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted 0-2R^(4b), and 5-6 membered heterocyclic system comprising carbon atoms andfrom 1-4 heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-2 R^(4b); R^(2a), at each occurrence, is selectedfrom H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted0-2 R^(4b), and 5-6 membered heterocyclic system comprising carbon atomsand from 1-4 heteroatoms selected from the group consisting of N, O, andS substituted with 0-2 R^(4b); R^(2b), at each occurrence, is selectedfrom CF₃, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(4b), and 5-6 membered heterocyclic systemcomprising carbon atoms and from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-2 R^(4b); R^(2c), at eachoccurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl,C₃₋₆ carbocyclic residue substituted 0-2 R^(4b), and 5-6 memberedheterocyclic system comprising carbon atoms and from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted 0-2R^(4b); alternatively, R² and R^(2a) combine to form a 5 or 6 memberedsaturated, partially saturated or unsaturated ring substituted 0-2R^(4b) which comprises from 0-1 additional heteroatoms selected from thegroup consisting of N, O, and S; R³, at each occurrence, is selectedfrom H, C₁₋₄ alkyl, and phenyl; R^(3a), at each occurrence, is selectedfrom H, C₁₋₄ alkyl, and phenyl; A is selected from: C₃₋₁₀ carbocyclicresidue substituted 0-2 R⁴, and 5-10 membered heterocyclic systemcomprising carbon atoms and from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted 0-2 R⁴; B is selected from: X—Y,NR²R^(2a), C(═NR²)NR²R^(2a), NR²C(═NR²)NR²R^(2a), C₃₋₁₀ carbocyclicresidue substituted with 0-2 R^(4a), and 5-10 membered heterocyclicsystem comprising carbon atoms and from 1-4 heteroatoms selected fromthe group consisting of N, O, and S substituted 0-2 R^(4a); X isselected from C₁₋₄ alkylene, —CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—,—C(═NR)—, —CR²(NR^(1″)R²)—, —CR²(OR²)—, —CR²(SR²)—, —C(O)CR²R^(2a)—,—CR²R^(2a)C(O), —S(O)_(p)—, —S(O)_(p)CR²R^(2a)—, —CR²R^(2a)S(O)_(p)—,—S(O)₂NR²—, —NR²S(O)₂—, —NR²S(O)₂CR²R^(2a)—, —CR²R^(2a)S(O)₂NR²—,—NR²S(O)₂NR²—, —C(O)NR²—, —NR²C(O)—, —C(O)NR²CR²R^(2a)—,—NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—, —NR²C(O)O—,—OC(O)NR²—, —NR²C(O)NR²—, —NR²—, —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O,—CR²R^(2a)O—, and OCR²R^(2a)—; Y is selected from: (CH₂)_(r)NR²R^(2a),provided that X—Y do not form a N—N, O—N, or S—N bond, C₃₋₁₀ carbocyclicresidue substituted 0-2 R^(4a), and 5-10 membered heterocyclic systemcomprising carbon atoms and from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted 0-2 R^(4a); R⁴, at eachoccurrence, is selected from ═O, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, —CN,NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b),C(O)NR²R^(2a), NR²C(O)NR²R^(2a), CH(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a),SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂-C₁₋₄ NR²SO₂R⁵, S(O)_(p)R⁵,(CF₂)_(r)CF₃, NCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″),N(CH₂)₂(CH₂)_(t)R^(1′), O(CH₂)₂(CH₂)_(t)R^(1′), andS(CH₂)₂(CH₂)_(t)R^(1′), alternatively, one R⁴ is a 5-6 membered aromaticheterocycle comprising carbon atoms and from 1-4 heteroatoms selectedfrom the group consisting of N, O, and S; R^(4a), at each occurrence, isselected from ═O, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, —CN, NO₂,(CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a),NR²C(O)NR²R^(2a), CH(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a),NR²SO₂NR²R^(2a), NR²SO₂-C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and(CF₂)_(r)CF₃; alternatively, one R^(4a) is a 5-6 membered aromaticheterocycle comprising carbon atoms and from 1-4 heteroatoms selectedfrom the group consisting of N, O, and S substituted with 0-R⁵; R^(4b),at each occurrence, is selected from ═O, (CH₂)_(r)OR³, halo, C₁₋₄ alkyl,—CN, NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³, NR³C(O)R^(3a),C(O)NR³R^(3a), NR³C(O)NR³R^(3a), CH(═NR³)NR³R^(3a), NH³C(═NR³)NR³R^(3a),SO₂NR³R^(3a), NR³SO₂NR³R^(3a), NR³SO₂-C₁₋₄ alkyl, NR³SO₂CF₃,NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)-C₁₋₄ alkyl, S(O)_(p)-phenyl, and(CF₂)_(r)CF₃; R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl,phenyl substituted 0-2 R⁶, and benzyl substituted 0-2 R⁶; R⁶, at eachoccurrence, is selected from H, OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, CN,NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b),NR²C(O)NR²R^(2a), CH(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a),NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₄ alkyl; R⁷, at each occurrence, isselected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄alkoxycarbonyl, (CH₂)_(n)-phenyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl,C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl,C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl,phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl; R⁸, at eachoccurrence, is selected from H, C₁₋₆ alkyl and (CH₂)_(n)-phenyl;alternatively, R⁷ and R⁸ combine to form a 5 or 6 membered saturated,ring which comprises from 0-1 additional heteroatoms selected from thegroup consisting of N, O, and S; R⁹, at each occurrence, is selectedfrom H, C₁₋₆ alkyl and (CH₂)_(n)-phenyl; n, at each occurrence, isselected from 0, 1, 2, and 3; m, at each occurrence, is selected from 0,1, and 2; p, at each occurrence, is selected from 0, 1, and 2; q, ateach occurrence is selected from 1 and 2; r, at each occurrence, isselected from 0, 1, 2, and 3; s, at each occurrence, is selected from 0,1, and 2; and, t, at each occurrence, is selected from 0 and 1 providedthat when a heterocyclic group is present it is other than a morpholine,pyrazine, primidine, pyridazine, piperidine, pyridine or tetrazole.
 2. Acompound according to claim 1, wherein the compound is of formula Ia:

wherein; Z is selected from a CH₂O, OCH₂, CH₂NH, NHCH₂, C(O), CH₂C(O),C(O)CH₂, NHC(O), C(O)NH, CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂,provided that Z does not form a N—N, N—O, NCH₂N, or NCH₂O bond withgroup A; A is selected from one of the following carbocyclic andheterocyclic systems which are substituted 0-2 R⁴: phenyl, piperidinyl,piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl,pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl,benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl,indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl; B isselected from: Y, X—Y, NR²R^(2a), C(═NR²)NR²R^(2a), andNR²C(═NR²)NR²R^(2a); X is selected from C₁₋₄ alkylene, —C(O)—, —C(═NR)—,—CR²(NR²R^(2a))—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —C(O)NR²—, —NR²C(O)—,—C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—,—CR²R^(2a)NR²C(O)—, —NR²C(O)NR²—, —NR²—, —NR²CR²R^(2a)—, —CR²R^(2a)NR²—,O, —CR²R^(2a)O—, and —OCR²R^(2a)—; Y is NR²R^(2a), provided that X—Y donot form a N—N or O—N bond; alternatively, Y is selected from one of thefollowing carbocyclic and heterocyclic systems which are substituted 0-2R^(4a): cylcopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl,piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl,pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl,isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl,benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl,indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;alternatively, Y is selected from the following bicyclic heteroaryl ringsystems:

K is selected from O, S, NH, and N.
 3. A compound according to claim 2,wherein; Z is selected from a C(O), CH₂C(O), C(O)CH₂, NHC(O), C(O)NH,C(O)N(CH₃), CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided that Z doesnot form a N—N or NCH₂N bond with group A.
 4. A compound according toclaim 3, wherein; E is phenyl substituted with R or 2-pyridylsubstituted with R; D is selected from C(O)NH₂, C(═NH)NH₂, CH₂NH₂,CH₂NHCH₃, CH(CH₃)NH₂, and C(CH₃)₂NH₂; and, R is selected from H, OCH₃,Cl, and F.
 5. A compound according to claim 4, wherein: D—E is selectedfrom 3-amidinophenyl, 3-aminomethylphenyl, 3-aminocarbonylphenyl,3-(methylaminomethyl)phenyl, 3-(1-aminoethyl)phenyl,3-(2-amino-2-propyl)phenyl, 4-chloro-3-amidinophenyl,4-chloro-3-aminomethylphenyl, 4-chloro-3(methylaminomethyl)phenyl,4-fluoro-3-amidinophenyl, 4-fluoro-3-aminomethylphenyl,4-fluoro-3-(methylaminomethyl)phenyl, 6-amidinopyrid-2-yl,6-aminomethylpyrid-2-yl, 6-aminocarbonylpyrid-2-yl,6-(methylaminomethyl)pyrid-2-yl, 6-(1-aminoethyl)pyrid-2-yl, and6-(2-amino-2-propyl)pyrid-2-yl.
 6. A compound according to claim 3,wherein: Z is C(O)CH₂ and CONH, provided that Z does not form a N—N bondwith group A; A is selected from phenyl, pyridyl, and pyrimidyl, and issubstituted 0-2 R⁴; and, B is selected from X—Y, phenyl, pyrrolidino,morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1R^(4a); R⁴, at each occurrence, is selected from OH, (CH₂)_(r)OR², halo,C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), and (CF₂)_(r)CF₃; R^(4a) is selectedfrom C₁₋₄ alkyl, CF₃, S(O)_(p)R⁵, SO₂NR²R^(2a), and 1-CF₃-tetrazol-2-yl;R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, andbenzyl; X is CH₂ or C(O); and, Y is selected from pyrrolidino andmorpholino.
 7. A compound according to claim 6, wherein; A is selectedfrom the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl,3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and2-methoxyphenyl; and, B is selected from the group: 2-CF₃-phenyl,2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl,2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl,2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1′-CF₃-tetrazol-2-yl)phenyl,4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl,2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.
 8. Acompound according to claim 3, wherein: E is phenyl substituted with Ror 2-pyridyl substituted with R; D is selected from C(O)NH₂, C(═NH)NH₂,CH₂NH₂, CH₂NHCH₃, CH(CH₃)NH₂, and C(CH₃)₂NH₂; and, R is selected from H,OCH₃, Cl, and F; Z is C(O)CH₂ and CONH, provided that Z does not form aN—N bond with group A; A is selected from phenyl, pyridyl, andpyrimidyl, and is substituted 0-2 R⁴; and, B is selected from X—Y,phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and issubstituted with 0-1 R^(4a); R⁴, at each occurrence, is selected fromOH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), and(CF₂)_(r)CF₃; R^(4a) is selected from C₁₋₄ alkyl, CF₃, S(O)_(p)R⁵,SO₂NR²R^(2a), and 1-CF₃-tetrazol-2-yl; R⁵, at each occurrence, isselected from CF₃, C₁₋₆ alkyl, phenyl, and benzyl; X is CH₂ or C(O);and, Y is selected from pyrrolidino and morpholino.
 9. A compoundaccording to claim 8 wherein: D—E is selected from 3-amidinophenyl,3-aminomethylphenyl, 3-aminocarbonylphenyl, 3-(methylaminomethyl)phenyl,3-(1-aminoethyl)phenyl, 3-(2-amino-2-propyl)phenyl,4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl,4-chloro-3-(methylaminomethyl)phenyl, 4-fluoro-3-amidinophenyl,4-fluoro-3-aminomethylphenyl, 4-fluoro-3-(methylaminomethyl)phenyl,6-amidinopyrid-2-yl, 6-aminomethylpyrid-2-yl, 6-aminocarbonylpyrid-2-yl,6-(methylaminomethyl)pyrid-2-yl, 6-(1-aminoethyl)pyrid-2-yl,6-(2-amino-2-propyl)pyrid-2-yl; A is selected from the group: phenyl,2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl,3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and, Bis selected from the group: 2-CF₃-phenyl, 2-(aminosulfonyl)phenyl,2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl,1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino,2-(1′-CF₃-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl,2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl,2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.
 10. Acompound according to claim 9, wherein the compound is of formula Ia.11. A compound according to claim 9, wherein the compound is of formulaIb.
 12. A compound according to claim 3, wherein: D is selected fromC(═NR⁸)NR⁷R⁹, C(O)NR⁷R⁸, NR⁷R⁸, and CH₂NR⁷R⁸; E is phenyl substitutedwith R or pyridyl substituted with R; R is selected from H, Cl, F, OR³,CH₃, CH₂CH₃, OCF₃, and CF₃; Z is selected from C(O), CH₂C(O), C(O)CH₂,NHC(O), and C(O)NH, provided that Z does not form a N—N bond with groupA; R^(1a) and R^(1b) are, at each occurrence, independently selectedfrom H, —(CH₂)_(r)—R^(1′), NCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″),N(CH₂)₂(CH₂)_(t)R^(1′), O(CH₂)₂(CH₂)_(t)R^(1′), andS(CH₂)₂(CH₂)_(t)R^(1′); R^(1c) is selected from H, —(CH₂)_(q)—R^(1′),C₁₋₃ alkyl, C(O)R^(2c), (CF₂)_(r)CO₂R^(2c), and C(O)NR²R^(2a); R^(1′),at each occurrence, is selected from H, C₁₋₃ alkyl, halo, (CF₂)_(r)CF₃,OR², NR²R^(2a), C(O)R^(2c), (CF₂)_(r)CO₂R^(2c), S(O)_(p)R^(2b),NR²(CH₂)_(r)OR², NR²C(O)R^(2b), NR²C(O)₂R^(2b), C(O)NR²R^(2a),SO₂NR²R^(2a), and NR²SO₂R^(2b); A is selected from one of the followingcarbocyclic and heterocyclic systems which are substituted with 0-2 R⁴:phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl,morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl; B is selected from:Y, X—Y, NR²R^(2a), C(═NR²)NR²R^(2a), and NR²C(═NR²)NR²R^(2a); X isselected from CH₂, —CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—, —C(═NR)—,—CH(NR²R^(2a))—, —C(O)NR₂—, —NR²C(O)—, —NR²C(O)NR²—, —NR²—, and O; Y isNR²R^(2a), provided that X—Y do not form a N—N or O—N bond;alternatively, Y is selected from one of the following carbocyclic andheterocyclic systems which are substituted with 0-2 R^(4a): phenyl,piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl,thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl,thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl;R⁴, at each occurrence, is selected from ═O, OH, Cl, F, C₁₋₄ alkyl,(CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a),CH(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂-C₁₋₄ alkyl, NR²SO₂R⁵,S(O)_(p)R⁵, and (CF₂)_(r)CF₃; R^(4a), at each occurrence, is selectedfrom ═O, OH, Cl, F, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b),NR²C(O)R^(2b), C(O)NR²R^(2a), CH(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a),NR²SO₂-C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃, and1-CF₃-tetrazol-2-yl; R⁵, at each occurrence, is selected from CF₃, C₁₋₆alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 0-2R⁶; R⁶, at each occurrence, is selected from H, ═O, OH, OR², Cl, F, CH₃,CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b),CH(═NH)NH₂, NHC(═NH)NH₂, and SO₂NR²R^(2a); R⁷, at each occurrence, isselected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄alkoxycarbonyl, benzyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl,phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl; R⁸, at eachoccurrence, is selected from H, C₁₋₆ alkyl and benzyl; andalternatively, R⁷ and R⁸ combine to form a morpholino group; and, R⁹, ateach occurrence, is selected from H, C₁₋₆ alkyl and benzyl.
 13. Acompound according to claim 12, wherein; E is phenyl substituted with Ror 2-pyridyl substituted with R; R is selected from H, Cl, F, OCH₃, CH₃,OCF₃, and CF₃; Z is selected from a C(O)CH₂ and C(O)NH, provided that Zdoes not form a N—N bond with group A; R^(1a), at each occurrence, isselected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a),S(O)_(p)R^(2b), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c),CH₂C(O)R^(2c), C(O)NR²R^(2a), and SO₂NR²R^(2a); R^(1b) is selected fromH, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a), S(O)_(p)R^(2b),CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c),C(O)NR²R^(2a), and SO₂NR²R^(2a); R^(1c) is selected from H, CH₃, CH₂CH₃,CF₃, CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c),and C(O)NR²R^(2a); A is selected from one of the following carbocyclicand heterocyclic systems which are substituted with 0-2 R⁴; phenyl,pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl; B is selected from:Y and X—Y; X is selected from CH₂, —CR²(CR²R^(2b))—, —C(O)—, —C(═NR)—,—CH(NR²R^(2a))—, —C(O)NR²—, —NR²C(O)—, —NR²C(O)NR²—, —NR²—, and O; Y isNR²R^(2a), provided that X—Y do not form a N—N or O—N bond;alternatively, Y is selected from one of the following carbocyclic andheterocyclic systems which are substituted with 0-2 R^(4a); phenyl,piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl,thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl;R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, andphenyl; R^(2a), at each occurrence, is selected from H, CF₃, CH₃,benzyl, and phenyl; R^(2b), at each occurrence, is selected from CF₃,OCH₃, CH₃, benzyl, and phenyl; R^(2c), at each occurrence, is selectedfrom CF₃, OH, OCH₃, CH₃, benzyl, and phenyl; alternatively, R² and R²acombine to form a 5 or 6 membered saturated, partially unsaturated, orunsaturated ring which comprises from 0-1 additional heteroatomsselected from the group consisting of N, O, and S; R³, at eachoccurrence, is selected from H, CH₃, CH₂CH₃, and phenyl; R^(3a), at eachoccurrence, is selected from H, CH₃, CH₂CH₃, and phenyl; R⁴, at eachoccurrence, is selected from OH, Cl, F, CH₃, CH₂CH₃, NR²R^(2a),CH₂NR²R^(2a), C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a), and CF₃; R^(4a),at each occurrence, is selected from OH, Cl, F, CH₃, CH₂CH₃, NR²R^(2a),CH₂NR²R^(2a), C(O)R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R⁵, CF₃,and 1-CF₃-tetrazol-2-yl; R⁵, at each occurrence, is selected from CF₃,C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with1 R⁶; R⁶, at each occurrence, is selected from H, OH, OCH₃, Cl, F, CH₃,CN, NO₂, NR²R^(2a), CH₂NR²R^(2a), and SO₂NR²R^(2a); R⁷, at eachoccurrence, is selected from H, OH, C₁₋₃ alkyl, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxy, C₁₋₄ alkoxycarbonyl, benzyl, phenoxy, phenoxycarbonyl,benzylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl,phenylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl,phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl; R⁸, at eachoccurrence, is selected from H, CH₃, and benzyl; and, alternatively, R⁷and R⁸ combine to form a morpholino group; R⁹, at each occurrence, isselected from H, CH₃, and benzyl.
 14. A compound according to claim 13,wherein: R^(1a), at each occurrence, is selected from H, CH₃, CH₂CH₃,Cl, F, CF₃, OCH₃, NR²R^(2a), S(O)_(p)R^(2b), C(O)NR²R^(2a),CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c), andSO₂NR²R^(2a); R^(1b) is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃,NR²R^(2a), S(O)_(p)R^(2b), C(O)NR²R^(2a), CH₂S(O)_(p)R^(2b),CH₂NR²S(O)_(p)R^(2b), C(O)R^(2b), CH₂C(O)R^(2b), and SO₂NR²R^(2a);R^(1c) is selected from H, CH₃, CH₂CH₃, CF₃, C(O)NR²R^(2a),CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2b), and CH₂C(O)R^(2b);A is selected from one of the following carbocyclic and heterocyclicsystems which are substituted with 0-2 R⁴; phenyl, pyridyl, andpyrimidyl; B is selected from: Y and X—Y; X is selected from —C(O)— andO; Y is NR²R^(2a), provided that X—Y do not form a O—N bond;alternatively, Y is selected from one of the following carbocyclic andheterocyclic systems which are substituted with 0-2 R^(4a): phenyl,piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl,and 1,2,3-triazolyl; R², at each occurrence, is selected from H, CF₃,CH₃, benzyl, and phenyl; R^(2a), at each occurrence, is selected from H,CF₃, CH₃, benzyl, and phenyl; R^(2b), at each occurrence, is selectedfrom CF₃, OCH₃, CH₃, benzyl, and phenyl; R^(2c), at each occurrence, isselected from CF₃, OH, OCH₃, CH₃, benzyl, and phenyl; alternatively, R²and R^(2a) combine to form a ring system selected from pyrrolidinyl,piperazinyl and morpholino; R⁴, at each occurrence, is selected from Cl,F, CH₃, NR²R^(2a), and CF₃; R^(4a), at each occurrence, is selected fromCl, F, CH₃, SO₂NR²R^(2a), S(O)_(p)R⁵, and CF₃; and, R⁵, at eachoccurrence, is selected from CF₃ and CH₃.
 15. A compound according toclaim 1, wherein the compound is selected from the group:1-(3-amidinophenyl)-5-[[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)-aminocarbonyl]-3-trifluoromethyl-pyrazoline;and,1-(3-aminomethylphenyl)-5-[[(2′-methylsulfonyl-[1,1′]-biphen-4-yl)-aminocarbonyl]-3-trifluoromethyl-pyrazoline;and pharmaceutically acceptable salts thereof.
 16. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof.
 17. A method for treating athromboembolic disorder, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound according toclaim 1 or a pharmaceutically acceptable salt thereof.
 18. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 2 or a pharmaceutically acceptable salt thereof.
 19. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 3 or a pharmaceutically acceptable salt thereof.
 20. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 4 or a pharmaceutically acceptable salt thereof.
 21. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 5 or a pharmaceutically acceptable salt thereof.
 22. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 6 or a pharmaceutically acceptable salt thereof.
 23. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 7 or a pharmaceutically acceptable salt thereof.
 24. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 8 or a pharmaceutically acceptable salt thereof.
 25. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 9 or a pharmaceutically acceptable salt thereof.
 26. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 10 or a pharmaceutically acceptable salt thereof.
 27. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 11 or a pharmaceutically acceptable salt thereof.
 28. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 12 or a pharmaceutically acceptable salt thereof.
 29. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 13 or a pharmaceutically acceptable salt thereof.
 30. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 14 or a pharmaceutically acceptable salt thereof.
 31. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 15 or a pharmaceutically acceptable salt thereof.
 32. A methodfor treating a thromboembolic disorder, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundaccording to claim 2 or a pharmaceutically acceptable salt thereof. 33.A method for treating a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound according to claim 3 or a pharmaceuticallyacceptable salt thereof.
 34. A method for treating a thromboembolicdisorder, comprising: administering to a patient in need thereof atherapeutically effective amount of a compound according to claim 4 or apharmaceutically acceptable salt thereof.
 35. A method for treating athromboembolic disorder, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound according toclaim 5 or a pharmaceutically acceptable salt thereof.
 36. A method fortreating a thromboembolic disorder, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundaccording to claim 6 or a pharmaceutically acceptable salt thereof. 37.A method for treating a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound according to claim 7 or a pharmaceuticallyacceptable salt thereof.
 38. A method for treating a thromboembolicdisorder, comprising: administering to a patient in need thereof atherapeutically effective amount of a compound according to claim 8 or apharmaceutically acceptable salt thereof.
 39. A method for treating athromboembolic disorder, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound according toclaim 9 or a pharmaceutically acceptable salt thereof.
 40. A method fortreating a thromboembolic disorder, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundaccording to claim 10 or a pharmaceutically acceptable salt thereof. 41.A method for treating a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound according to claim 11 or a pharmaceuticallyacceptable salt thereof.
 42. A method for treating a thromboembolicdisorder, comprising: administering to a patient in need thereof atherapeutically effective amount of a compound according to claim 12 ora pharmaceutically acceptable salt thereof.
 43. A method for treating athromboembolic disorder, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound according toclaim 13 or a pharmaceutically acceptable salt thereof.
 44. A method fortreating a thromboembolic disorder, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundaccording to claim 14 or a pharmaceutically acceptable salt thereof. 45.A method for treating a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound according to claim 15 or a pharmaceuticallyacceptable salt thereof.